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Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 175
5
Summary and Conclusion
In the past decade there has been renewed attention and interest in the use of
traditional medicine (Ayurveda Yoga Naturopathy Unani Siddha and Homeopathy)
in India and globally It is estimated that 65 of the population in rural India use
medicinal plants to meet primary health care needs So it is the cardinal responsibility
of the regulatory authorities to ensure that the consumers get the medication with
guarantee which includes purity safety potency and efficacy Modern medicine
which is continuously undergoing metabolic changes and improvements in the
standard of purity safety and efficacy Thus maintaining the quality of Herbal
medication becomes the sole responsibility of the manufacturer and scientists
working in this field
Plant material and herbal remedies derived from them represent substantial portion of
global market and in this respect internationally recognized guidelines for their
quality assessment and quality control are necessary The traditional medicine
(Ayurveda Yoga Naturopathy Unani Siddha and Homeopathy) have been given
due recognition by the regulatory bodies in the recent past Recently many
international authorities and agencies including the world health organization
European Agencies for the evaluation of medicinal product and European Scientific
Co-operation of phyto-medicine US Agencies for Health Care Policy and Research
European Pharmacopoeia Commission department of Indian System of Medicine
have started creating a new mechanism to induce quality control and standardization
of traditional medicine WHO has emphasized the need to ensure quality control of
medicinal plant products by using modern technique and by applying suitable
parameters and standards
Patent proprietary Ayurvedic medicines are sold over the counter in pharmacies
These products appear to represent a major share of branded traditional medicine in
India Nevertheless systems like Ayurveda still need to gain an empirical support of
modern medical sciences to make them credible and acceptable for all in this regard
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 176
it is a need to develop the modern dosage form like Tablet Mouth Dissolving Tablets
and Capsules of traditional dosage form (vati gutika churna or safoof etc) with
respect to increase the stability dose accuracy production rate quality of packaging
material elegance of design overall aesthetic appeal and so on Some innovative
research efforts are required to define the advantages of standardization and
development of modern dosage form to make the herbal drug acceptable globally
The present study is an approach to develop quality control parameters and
development of modern dosage form (Capsule) of identified formulations viz
Balacaturbhadrika churna (Ayurvedic) Shingyadi churna (Ayurvedic) Thirikadu
choornam (Siddha) and Safoof-E-Sana (Unani) which are official in their respective
formularies
51 Standardization of Balacaturbhadrika churna
Balacaturbhadrika churna is a fine powder form which is widely used in Diarrhoea
Fever Cough and Asthma at dose of 500 mg to 1 gmday It is composed of Cyperus
rotundus (musta) Piper longum (pippali) Aconitum heterophy (ativisa) and Pistacia
integerrima (sringi) All the ingredients are firstly powdered separately and mixed
together All the plant raw materials were purchased from the local market of Raipur
CG and identified morphologically and microscopically and compared with standard
pharmacopoeial monograph All the reagents and solvents used were of analytical
grade The sample of crude drug was also authenticated by University Institute of
Pharmacy Pandit Ravishankar Shukla University Raipur The ash values extractive
values with various reagents were determined as per the WHO guidelines
Three batches of Balacaturbhadrika churna designated as BC-I BC-II and BC-III
were prepared in laboratory using method described in Ayurvedic Formulary of India
Evaluation of organoleptic characters of raw materials Ghana (musta) Krsna
(pippali) Aruna (ativisa) and Sringi (karkatasringi) was performed and characters are
recorded Laboratory batches of Balacaturbhadrika churna (BC-I BC-II and BC-III)
and one marketed preparations were also evaluated for organoleptic characters The
results for the marketed formulation (MF) and Laboratory formulations (LF) are
found comparable
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 177
The moisture content of formulation was within acceptable range (lt8) thus
implying that the formulation can be stored for a long period and would not easily be
attacked by microbes Physical properties namely tapped density bulk density angle
of repose hausner ratio and carrrsquos index were calculated for Lab formulation
marketed formulation and its raw materials The value of angle of repose for raw
materials Cyperus rotundus Piper longum Aconitum heterophy Pistacia
integerrima lab formulation (BC-I) and marketed formulation were 2862 3128
2986 2434 2736 and 2745 respectively which shows good flow properties of
prepared lab formulation The flow properties of lab (BC-I) and marketed
formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos index it was found
125 20 and 119 16 respectively and indicates good flow characteristics
Results of the phytochemical screening of the raw materials lab formulation and
marketed formulation of Balacaturbhadrika churna were concluded One notable
difference as a result of the method of extraction is the alkaloids in Piper longum and
Pistacia integerrima are more soluble in ethanol than aqueous extract We were
performed more than one test for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated seven namely carbohydrate glycosides
tannins flavonoids fixed oil and proteins were detected in the ethanolic extract of lab
and marketed formulations however the aqueous extracts of both formulations shows
the presence of saponins with previously stated seven phytochemical groups Steroids
were absent in all the ingredients and formulations for both methods of extraction
Total ash value of Cyperus rotundus Piper longum Aconitum heterophy Pistacia
integerrima lab formulation (BC-I) and marketed formulation were found
7346plusmn0346 5032plusmn0624 2981plusmn0243 4621plusmn0334 8148plusmn0337 and
19633plusmn0552 respectively The value of total ash in marketed formulation is
comparatively high in comparison to lab formulation may be because of the higher
amounts of inorganic components present in marketed formulation
Alcohol-soluble and water soluble extractive values of ingredients and formulations
were performed as per WHO guidelines Higher ethanol-soluble extractive value
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 178
(39294plusmn2226 and 30662plusmn0472 for lab and marketed formulations respectively)
implies that ethanol is a better solvent of extraction for the formulation than water
Arsenic and heavy metals are below the specified limit in all ingredients lab and
marketed formulations Tests were also performed for specific pathogen as per the
WHO (1998) guidelines E coli Salmonella species and S aureus were found absent
This ensures the level of safety of formulation
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Balacaturbhadrika
churna and powder of Piper longum (Pippali) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241
ww in Piper longum The content of piperine in different batches of
Balacaturbhadrika churna was found to be 0435 plusmn 0030 0424 plusmn 0001 0430 plusmn
0004 and 0346 plusmn 0002 ww respectively for lab formulation (BC-I BC-II BC-
III) and marketed formulation (MF) Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Balacaturbhadrika churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Balacaturbhadrika
churna by simple high-performance liquid chromatography (HPLC) determination
using piperine as a standard which are important and major content in formulation
RP- HPLC methods for simultaneous determination of piperine have been developed
A C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary
gradient mode with mobile phase methanol at flow rate is 10mlmin used and
effluent was monitored at 343 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0124 0435 plusmn 0025 0424 plusmn 0241 0430 plusmn 0262 and 0346
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 179
plusmn 0762 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
HPTLC fingerprinting method
HPTLC fingerprint method for Balacaturbhadrika churna using piperine as a standard
is developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine was
found to be 192 plusmn 008 0442 plusmn 0005 0431 plusmn 0023 0430 plusmn 0081 and 0362 plusmn
0242 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Balacaturbhadrika churna
Stability studies
During accelerated stability studies as per WHO (1998) physicochemical parameters
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
52 Standardization of Shringyadi churna
Shringyadi churna is an Ayurvedic alternative medicine which is used in diarrhea
fever cough and asthma It composed of dried powders of Pistacia integerrima
(karkatasringi) Piper longum (pippali) and Aconitum palmatum (ativisa)
All the ingredients are firstly powdered separately and mixed together All the plant
raw materials were purchased from the local market of Raipur CG and identified
morphologically and microscopically and compared with standard pharmacopoeial
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 180
monograph The sample of crude drug was also authenticated by University Institute
of Pharmacy Pandit Ravishankar Shukla University Raipur All the reagents and
solvents used were of analytical grade The ash values extractive values with various
reagents and were determined as per the WHO guidelines Three batches of
Shringyadi churna designated as SC-I SC-II and SC-III were prepared in laboratory
using method described in Ayurvedic Formulary of India Evaluation of organoleptic
characters of raw materials Pistacia integerrima (karkatasringi) Piper longum
(pippali) and Aconitum palmatum (ativisa) were performed and characters are
recorded
Laboratory batches of Shringyadi churna (SC-I SC-II and SC-III) and one marketed
preparations were also evaluated for organoleptic characters The results for the
marketed formulations M I and Laboratory formulation are found comparable
The moisture content of formulation was within acceptable range that is 224plusmn0242
and 232plusmn0282 for lab and marketed formulations respectively thus implying that the
formulation can be stored for a long period and would not easily be attacked by
microbes Physical properties namely tapped density bulk density angle of repose
hausner ratio and carrrsquos index were calculated for Lab formulation marketed
formulation and its raw materials The value of angle of repose for raw materials
Pistacia integerrima Piper longum Aconitum palmatum lab formulation (SC-I) and
marketed formulation were 2434 3128 2986 2686 and 2542 respectively which
shows good flow properties of prepared lab formulation The flow properties of lab
(SC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos
index it was found 125 20 and 123 19 respectively and indicates good flow
characteristics
Seven phytochemical groups namely carbohydrate glycosides tannins flavonoids
fixed oil and proteins were detected in the ethanolic extract of lab and marketed
formulations however the aqueous extracts of both formulations shows the presence
of saponins with previously stated seven phytochemical groups Steroids were absent
in all the ingredients and formulations for both methods of extraction Results also
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
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Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
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Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
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Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
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Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200340(6)333-39
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Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Lange D Europersquos medicinal and aromatic plants their use trade and
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO 2003 WHO guidelines on good agricultural and collection practices
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Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
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dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q16
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Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 176
it is a need to develop the modern dosage form like Tablet Mouth Dissolving Tablets
and Capsules of traditional dosage form (vati gutika churna or safoof etc) with
respect to increase the stability dose accuracy production rate quality of packaging
material elegance of design overall aesthetic appeal and so on Some innovative
research efforts are required to define the advantages of standardization and
development of modern dosage form to make the herbal drug acceptable globally
The present study is an approach to develop quality control parameters and
development of modern dosage form (Capsule) of identified formulations viz
Balacaturbhadrika churna (Ayurvedic) Shingyadi churna (Ayurvedic) Thirikadu
choornam (Siddha) and Safoof-E-Sana (Unani) which are official in their respective
formularies
51 Standardization of Balacaturbhadrika churna
Balacaturbhadrika churna is a fine powder form which is widely used in Diarrhoea
Fever Cough and Asthma at dose of 500 mg to 1 gmday It is composed of Cyperus
rotundus (musta) Piper longum (pippali) Aconitum heterophy (ativisa) and Pistacia
integerrima (sringi) All the ingredients are firstly powdered separately and mixed
together All the plant raw materials were purchased from the local market of Raipur
CG and identified morphologically and microscopically and compared with standard
pharmacopoeial monograph All the reagents and solvents used were of analytical
grade The sample of crude drug was also authenticated by University Institute of
Pharmacy Pandit Ravishankar Shukla University Raipur The ash values extractive
values with various reagents were determined as per the WHO guidelines
Three batches of Balacaturbhadrika churna designated as BC-I BC-II and BC-III
were prepared in laboratory using method described in Ayurvedic Formulary of India
Evaluation of organoleptic characters of raw materials Ghana (musta) Krsna
(pippali) Aruna (ativisa) and Sringi (karkatasringi) was performed and characters are
recorded Laboratory batches of Balacaturbhadrika churna (BC-I BC-II and BC-III)
and one marketed preparations were also evaluated for organoleptic characters The
results for the marketed formulation (MF) and Laboratory formulations (LF) are
found comparable
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 177
The moisture content of formulation was within acceptable range (lt8) thus
implying that the formulation can be stored for a long period and would not easily be
attacked by microbes Physical properties namely tapped density bulk density angle
of repose hausner ratio and carrrsquos index were calculated for Lab formulation
marketed formulation and its raw materials The value of angle of repose for raw
materials Cyperus rotundus Piper longum Aconitum heterophy Pistacia
integerrima lab formulation (BC-I) and marketed formulation were 2862 3128
2986 2434 2736 and 2745 respectively which shows good flow properties of
prepared lab formulation The flow properties of lab (BC-I) and marketed
formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos index it was found
125 20 and 119 16 respectively and indicates good flow characteristics
Results of the phytochemical screening of the raw materials lab formulation and
marketed formulation of Balacaturbhadrika churna were concluded One notable
difference as a result of the method of extraction is the alkaloids in Piper longum and
Pistacia integerrima are more soluble in ethanol than aqueous extract We were
performed more than one test for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated seven namely carbohydrate glycosides
tannins flavonoids fixed oil and proteins were detected in the ethanolic extract of lab
and marketed formulations however the aqueous extracts of both formulations shows
the presence of saponins with previously stated seven phytochemical groups Steroids
were absent in all the ingredients and formulations for both methods of extraction
Total ash value of Cyperus rotundus Piper longum Aconitum heterophy Pistacia
integerrima lab formulation (BC-I) and marketed formulation were found
7346plusmn0346 5032plusmn0624 2981plusmn0243 4621plusmn0334 8148plusmn0337 and
19633plusmn0552 respectively The value of total ash in marketed formulation is
comparatively high in comparison to lab formulation may be because of the higher
amounts of inorganic components present in marketed formulation
Alcohol-soluble and water soluble extractive values of ingredients and formulations
were performed as per WHO guidelines Higher ethanol-soluble extractive value
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 178
(39294plusmn2226 and 30662plusmn0472 for lab and marketed formulations respectively)
implies that ethanol is a better solvent of extraction for the formulation than water
Arsenic and heavy metals are below the specified limit in all ingredients lab and
marketed formulations Tests were also performed for specific pathogen as per the
WHO (1998) guidelines E coli Salmonella species and S aureus were found absent
This ensures the level of safety of formulation
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Balacaturbhadrika
churna and powder of Piper longum (Pippali) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241
ww in Piper longum The content of piperine in different batches of
Balacaturbhadrika churna was found to be 0435 plusmn 0030 0424 plusmn 0001 0430 plusmn
0004 and 0346 plusmn 0002 ww respectively for lab formulation (BC-I BC-II BC-
III) and marketed formulation (MF) Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Balacaturbhadrika churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Balacaturbhadrika
churna by simple high-performance liquid chromatography (HPLC) determination
using piperine as a standard which are important and major content in formulation
RP- HPLC methods for simultaneous determination of piperine have been developed
A C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary
gradient mode with mobile phase methanol at flow rate is 10mlmin used and
effluent was monitored at 343 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0124 0435 plusmn 0025 0424 plusmn 0241 0430 plusmn 0262 and 0346
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 179
plusmn 0762 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
HPTLC fingerprinting method
HPTLC fingerprint method for Balacaturbhadrika churna using piperine as a standard
is developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine was
found to be 192 plusmn 008 0442 plusmn 0005 0431 plusmn 0023 0430 plusmn 0081 and 0362 plusmn
0242 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Balacaturbhadrika churna
Stability studies
During accelerated stability studies as per WHO (1998) physicochemical parameters
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
52 Standardization of Shringyadi churna
Shringyadi churna is an Ayurvedic alternative medicine which is used in diarrhea
fever cough and asthma It composed of dried powders of Pistacia integerrima
(karkatasringi) Piper longum (pippali) and Aconitum palmatum (ativisa)
All the ingredients are firstly powdered separately and mixed together All the plant
raw materials were purchased from the local market of Raipur CG and identified
morphologically and microscopically and compared with standard pharmacopoeial
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 180
monograph The sample of crude drug was also authenticated by University Institute
of Pharmacy Pandit Ravishankar Shukla University Raipur All the reagents and
solvents used were of analytical grade The ash values extractive values with various
reagents and were determined as per the WHO guidelines Three batches of
Shringyadi churna designated as SC-I SC-II and SC-III were prepared in laboratory
using method described in Ayurvedic Formulary of India Evaluation of organoleptic
characters of raw materials Pistacia integerrima (karkatasringi) Piper longum
(pippali) and Aconitum palmatum (ativisa) were performed and characters are
recorded
Laboratory batches of Shringyadi churna (SC-I SC-II and SC-III) and one marketed
preparations were also evaluated for organoleptic characters The results for the
marketed formulations M I and Laboratory formulation are found comparable
The moisture content of formulation was within acceptable range that is 224plusmn0242
and 232plusmn0282 for lab and marketed formulations respectively thus implying that the
formulation can be stored for a long period and would not easily be attacked by
microbes Physical properties namely tapped density bulk density angle of repose
hausner ratio and carrrsquos index were calculated for Lab formulation marketed
formulation and its raw materials The value of angle of repose for raw materials
Pistacia integerrima Piper longum Aconitum palmatum lab formulation (SC-I) and
marketed formulation were 2434 3128 2986 2686 and 2542 respectively which
shows good flow properties of prepared lab formulation The flow properties of lab
(SC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos
index it was found 125 20 and 123 19 respectively and indicates good flow
characteristics
Seven phytochemical groups namely carbohydrate glycosides tannins flavonoids
fixed oil and proteins were detected in the ethanolic extract of lab and marketed
formulations however the aqueous extracts of both formulations shows the presence
of saponins with previously stated seven phytochemical groups Steroids were absent
in all the ingredients and formulations for both methods of extraction Results also
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Addae-Mensah I 1992 Towards a Rational Scientific Basis for Herbal Medicine
ndash A phytochemistrsquos two-decade contribution Accra Ghana Universities Press
Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
B Aryavidyan 1998 11(3)164-67
Alam M Dasan KKS Rukmani B Purshothaman KK Bull Med Ethnobot Res
1985 6(2-4)133-40
Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
Ministry of Health and Family Welfare Department of Indian Systems of
Medicine and Homoeopathy New Delhi India
Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Bagul MS Rajani M Ind drugs 2005 42(1) 15-19
Bartram T 1995 Encyclopaedia of Herbal Medicine Grace Dorset
Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
Rockville 1995 Pp 165-178
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200414(4)207-13
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
Anal 2005 37937- 41
Ellenberger A First International Symposium on the Conservation of Medicinal
Plants in Trade in Europe TRAFFIC Europe Kew 1998 UK
Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
criteria for herbal substances herbal preparations and herbal medicinal
productstraditional herbal medicinal products European Medicines Agency
(EMEA) Committee for Medicinal Products for Human Use (CHMP) Committee
for Medicinal Products for Veterinary Use (CVMP) London UK
Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
proprietary medicinal products Off J 1965 22 369ndash373
Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
Farnsworth NR Bingel AS In Wagner H Wolff P (eds) New Natural Products
and Plant Drugs with Pharmacological Biological or Therapeutical Activity
Springer Berlin Germany 19771-22
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
Evaluation of Plants with Reference to the Malagasy Flora Monograph from the
IFS-NAPRECA Workshop on Bioassays Madagascar 1993 35ndash 43
Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
from Candidate Drug Selection to Commercial Dosage Form Boca Raton CRC
Press ISBN 1-57491-120-1
Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
for Conservation of Nature (IUCN) Gland 1994 Pp 50
Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
Food Chem 2003 51 375-382
Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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Jones RT Pharmaceutical Capsules 2nd edition Pharmaceutical Press London
2004 18-23
Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
conservation Traffic EuropeInternational Cambridge 1998 UK
Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mahrotra S Rawat A Singh HK Shome U Ethanobotany 1995 7(1amp2)1-15
Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
Phytosciences In Ahmad I Aqil F Owais M (eds) Modern Phytomedicine
Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
ethnobotany In Shrivastava MM Sanghi R (Eds) Chemistry for Green
Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
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Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
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Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
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with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
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Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
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Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
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[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
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6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 177
The moisture content of formulation was within acceptable range (lt8) thus
implying that the formulation can be stored for a long period and would not easily be
attacked by microbes Physical properties namely tapped density bulk density angle
of repose hausner ratio and carrrsquos index were calculated for Lab formulation
marketed formulation and its raw materials The value of angle of repose for raw
materials Cyperus rotundus Piper longum Aconitum heterophy Pistacia
integerrima lab formulation (BC-I) and marketed formulation were 2862 3128
2986 2434 2736 and 2745 respectively which shows good flow properties of
prepared lab formulation The flow properties of lab (BC-I) and marketed
formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos index it was found
125 20 and 119 16 respectively and indicates good flow characteristics
Results of the phytochemical screening of the raw materials lab formulation and
marketed formulation of Balacaturbhadrika churna were concluded One notable
difference as a result of the method of extraction is the alkaloids in Piper longum and
Pistacia integerrima are more soluble in ethanol than aqueous extract We were
performed more than one test for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated seven namely carbohydrate glycosides
tannins flavonoids fixed oil and proteins were detected in the ethanolic extract of lab
and marketed formulations however the aqueous extracts of both formulations shows
the presence of saponins with previously stated seven phytochemical groups Steroids
were absent in all the ingredients and formulations for both methods of extraction
Total ash value of Cyperus rotundus Piper longum Aconitum heterophy Pistacia
integerrima lab formulation (BC-I) and marketed formulation were found
7346plusmn0346 5032plusmn0624 2981plusmn0243 4621plusmn0334 8148plusmn0337 and
19633plusmn0552 respectively The value of total ash in marketed formulation is
comparatively high in comparison to lab formulation may be because of the higher
amounts of inorganic components present in marketed formulation
Alcohol-soluble and water soluble extractive values of ingredients and formulations
were performed as per WHO guidelines Higher ethanol-soluble extractive value
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 178
(39294plusmn2226 and 30662plusmn0472 for lab and marketed formulations respectively)
implies that ethanol is a better solvent of extraction for the formulation than water
Arsenic and heavy metals are below the specified limit in all ingredients lab and
marketed formulations Tests were also performed for specific pathogen as per the
WHO (1998) guidelines E coli Salmonella species and S aureus were found absent
This ensures the level of safety of formulation
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Balacaturbhadrika
churna and powder of Piper longum (Pippali) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241
ww in Piper longum The content of piperine in different batches of
Balacaturbhadrika churna was found to be 0435 plusmn 0030 0424 plusmn 0001 0430 plusmn
0004 and 0346 plusmn 0002 ww respectively for lab formulation (BC-I BC-II BC-
III) and marketed formulation (MF) Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Balacaturbhadrika churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Balacaturbhadrika
churna by simple high-performance liquid chromatography (HPLC) determination
using piperine as a standard which are important and major content in formulation
RP- HPLC methods for simultaneous determination of piperine have been developed
A C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary
gradient mode with mobile phase methanol at flow rate is 10mlmin used and
effluent was monitored at 343 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0124 0435 plusmn 0025 0424 plusmn 0241 0430 plusmn 0262 and 0346
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 179
plusmn 0762 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
HPTLC fingerprinting method
HPTLC fingerprint method for Balacaturbhadrika churna using piperine as a standard
is developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine was
found to be 192 plusmn 008 0442 plusmn 0005 0431 plusmn 0023 0430 plusmn 0081 and 0362 plusmn
0242 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Balacaturbhadrika churna
Stability studies
During accelerated stability studies as per WHO (1998) physicochemical parameters
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
52 Standardization of Shringyadi churna
Shringyadi churna is an Ayurvedic alternative medicine which is used in diarrhea
fever cough and asthma It composed of dried powders of Pistacia integerrima
(karkatasringi) Piper longum (pippali) and Aconitum palmatum (ativisa)
All the ingredients are firstly powdered separately and mixed together All the plant
raw materials were purchased from the local market of Raipur CG and identified
morphologically and microscopically and compared with standard pharmacopoeial
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 180
monograph The sample of crude drug was also authenticated by University Institute
of Pharmacy Pandit Ravishankar Shukla University Raipur All the reagents and
solvents used were of analytical grade The ash values extractive values with various
reagents and were determined as per the WHO guidelines Three batches of
Shringyadi churna designated as SC-I SC-II and SC-III were prepared in laboratory
using method described in Ayurvedic Formulary of India Evaluation of organoleptic
characters of raw materials Pistacia integerrima (karkatasringi) Piper longum
(pippali) and Aconitum palmatum (ativisa) were performed and characters are
recorded
Laboratory batches of Shringyadi churna (SC-I SC-II and SC-III) and one marketed
preparations were also evaluated for organoleptic characters The results for the
marketed formulations M I and Laboratory formulation are found comparable
The moisture content of formulation was within acceptable range that is 224plusmn0242
and 232plusmn0282 for lab and marketed formulations respectively thus implying that the
formulation can be stored for a long period and would not easily be attacked by
microbes Physical properties namely tapped density bulk density angle of repose
hausner ratio and carrrsquos index were calculated for Lab formulation marketed
formulation and its raw materials The value of angle of repose for raw materials
Pistacia integerrima Piper longum Aconitum palmatum lab formulation (SC-I) and
marketed formulation were 2434 3128 2986 2686 and 2542 respectively which
shows good flow properties of prepared lab formulation The flow properties of lab
(SC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos
index it was found 125 20 and 123 19 respectively and indicates good flow
characteristics
Seven phytochemical groups namely carbohydrate glycosides tannins flavonoids
fixed oil and proteins were detected in the ethanolic extract of lab and marketed
formulations however the aqueous extracts of both formulations shows the presence
of saponins with previously stated seven phytochemical groups Steroids were absent
in all the ingredients and formulations for both methods of extraction Results also
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
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Alderborn G Pharmaceutics the science of dosage form design 2nd edition
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Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
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Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
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Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
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Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
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Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
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Raina MK Indian J Nat Prod 1993 918-22
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Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
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95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
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Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
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Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
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Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
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The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
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The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
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WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 178
(39294plusmn2226 and 30662plusmn0472 for lab and marketed formulations respectively)
implies that ethanol is a better solvent of extraction for the formulation than water
Arsenic and heavy metals are below the specified limit in all ingredients lab and
marketed formulations Tests were also performed for specific pathogen as per the
WHO (1998) guidelines E coli Salmonella species and S aureus were found absent
This ensures the level of safety of formulation
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Balacaturbhadrika
churna and powder of Piper longum (Pippali) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241
ww in Piper longum The content of piperine in different batches of
Balacaturbhadrika churna was found to be 0435 plusmn 0030 0424 plusmn 0001 0430 plusmn
0004 and 0346 plusmn 0002 ww respectively for lab formulation (BC-I BC-II BC-
III) and marketed formulation (MF) Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Balacaturbhadrika churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Balacaturbhadrika
churna by simple high-performance liquid chromatography (HPLC) determination
using piperine as a standard which are important and major content in formulation
RP- HPLC methods for simultaneous determination of piperine have been developed
A C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary
gradient mode with mobile phase methanol at flow rate is 10mlmin used and
effluent was monitored at 343 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0124 0435 plusmn 0025 0424 plusmn 0241 0430 plusmn 0262 and 0346
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 179
plusmn 0762 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
HPTLC fingerprinting method
HPTLC fingerprint method for Balacaturbhadrika churna using piperine as a standard
is developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine was
found to be 192 plusmn 008 0442 plusmn 0005 0431 plusmn 0023 0430 plusmn 0081 and 0362 plusmn
0242 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Balacaturbhadrika churna
Stability studies
During accelerated stability studies as per WHO (1998) physicochemical parameters
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
52 Standardization of Shringyadi churna
Shringyadi churna is an Ayurvedic alternative medicine which is used in diarrhea
fever cough and asthma It composed of dried powders of Pistacia integerrima
(karkatasringi) Piper longum (pippali) and Aconitum palmatum (ativisa)
All the ingredients are firstly powdered separately and mixed together All the plant
raw materials were purchased from the local market of Raipur CG and identified
morphologically and microscopically and compared with standard pharmacopoeial
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 180
monograph The sample of crude drug was also authenticated by University Institute
of Pharmacy Pandit Ravishankar Shukla University Raipur All the reagents and
solvents used were of analytical grade The ash values extractive values with various
reagents and were determined as per the WHO guidelines Three batches of
Shringyadi churna designated as SC-I SC-II and SC-III were prepared in laboratory
using method described in Ayurvedic Formulary of India Evaluation of organoleptic
characters of raw materials Pistacia integerrima (karkatasringi) Piper longum
(pippali) and Aconitum palmatum (ativisa) were performed and characters are
recorded
Laboratory batches of Shringyadi churna (SC-I SC-II and SC-III) and one marketed
preparations were also evaluated for organoleptic characters The results for the
marketed formulations M I and Laboratory formulation are found comparable
The moisture content of formulation was within acceptable range that is 224plusmn0242
and 232plusmn0282 for lab and marketed formulations respectively thus implying that the
formulation can be stored for a long period and would not easily be attacked by
microbes Physical properties namely tapped density bulk density angle of repose
hausner ratio and carrrsquos index were calculated for Lab formulation marketed
formulation and its raw materials The value of angle of repose for raw materials
Pistacia integerrima Piper longum Aconitum palmatum lab formulation (SC-I) and
marketed formulation were 2434 3128 2986 2686 and 2542 respectively which
shows good flow properties of prepared lab formulation The flow properties of lab
(SC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos
index it was found 125 20 and 123 19 respectively and indicates good flow
characteristics
Seven phytochemical groups namely carbohydrate glycosides tannins flavonoids
fixed oil and proteins were detected in the ethanolic extract of lab and marketed
formulations however the aqueous extracts of both formulations shows the presence
of saponins with previously stated seven phytochemical groups Steroids were absent
in all the ingredients and formulations for both methods of extraction Results also
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Dasan KKS Rukmani B Purshothaman KK Bull Med Ethnobot Res
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Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
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Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
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Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
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Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
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Lange D Europersquos medicinal and aromatic plants their use trade and
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
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Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
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Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
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Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
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Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
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Formulations] 203
WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
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publisher and distributor 2004f88
References
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Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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Contents lists available at ScienceDirect
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 179
plusmn 0762 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
HPTLC fingerprinting method
HPTLC fingerprint method for Balacaturbhadrika churna using piperine as a standard
is developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine was
found to be 192 plusmn 008 0442 plusmn 0005 0431 plusmn 0023 0430 plusmn 0081 and 0362 plusmn
0242 ww respectively for Piper longum lab formulation (BC-I BC-II BC-III)
and marketed formulation (MF)
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Balacaturbhadrika churna
Stability studies
During accelerated stability studies as per WHO (1998) physicochemical parameters
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
52 Standardization of Shringyadi churna
Shringyadi churna is an Ayurvedic alternative medicine which is used in diarrhea
fever cough and asthma It composed of dried powders of Pistacia integerrima
(karkatasringi) Piper longum (pippali) and Aconitum palmatum (ativisa)
All the ingredients are firstly powdered separately and mixed together All the plant
raw materials were purchased from the local market of Raipur CG and identified
morphologically and microscopically and compared with standard pharmacopoeial
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 180
monograph The sample of crude drug was also authenticated by University Institute
of Pharmacy Pandit Ravishankar Shukla University Raipur All the reagents and
solvents used were of analytical grade The ash values extractive values with various
reagents and were determined as per the WHO guidelines Three batches of
Shringyadi churna designated as SC-I SC-II and SC-III were prepared in laboratory
using method described in Ayurvedic Formulary of India Evaluation of organoleptic
characters of raw materials Pistacia integerrima (karkatasringi) Piper longum
(pippali) and Aconitum palmatum (ativisa) were performed and characters are
recorded
Laboratory batches of Shringyadi churna (SC-I SC-II and SC-III) and one marketed
preparations were also evaluated for organoleptic characters The results for the
marketed formulations M I and Laboratory formulation are found comparable
The moisture content of formulation was within acceptable range that is 224plusmn0242
and 232plusmn0282 for lab and marketed formulations respectively thus implying that the
formulation can be stored for a long period and would not easily be attacked by
microbes Physical properties namely tapped density bulk density angle of repose
hausner ratio and carrrsquos index were calculated for Lab formulation marketed
formulation and its raw materials The value of angle of repose for raw materials
Pistacia integerrima Piper longum Aconitum palmatum lab formulation (SC-I) and
marketed formulation were 2434 3128 2986 2686 and 2542 respectively which
shows good flow properties of prepared lab formulation The flow properties of lab
(SC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos
index it was found 125 20 and 123 19 respectively and indicates good flow
characteristics
Seven phytochemical groups namely carbohydrate glycosides tannins flavonoids
fixed oil and proteins were detected in the ethanolic extract of lab and marketed
formulations however the aqueous extracts of both formulations shows the presence
of saponins with previously stated seven phytochemical groups Steroids were absent
in all the ingredients and formulations for both methods of extraction Results also
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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ndash A phytochemistrsquos two-decade contribution Accra Ghana Universities Press
Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
B Aryavidyan 1998 11(3)164-67
Alam M Dasan KKS Rukmani B Purshothaman KK Bull Med Ethnobot Res
1985 6(2-4)133-40
Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
Ministry of Health and Family Welfare Department of Indian Systems of
Medicine and Homoeopathy New Delhi India
Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Bagul MS Rajani M Ind drugs 2005 42(1) 15-19
Bartram T 1995 Encyclopaedia of Herbal Medicine Grace Dorset
Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
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Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200414(4)207-13
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
Anal 2005 37937- 41
Ellenberger A First International Symposium on the Conservation of Medicinal
Plants in Trade in Europe TRAFFIC Europe Kew 1998 UK
Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
criteria for herbal substances herbal preparations and herbal medicinal
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(EMEA) Committee for Medicinal Products for Human Use (CHMP) Committee
for Medicinal Products for Veterinary Use (CVMP) London UK
Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
proprietary medicinal products Off J 1965 22 369ndash373
Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
Farnsworth NR Bingel AS In Wagner H Wolff P (eds) New Natural Products
and Plant Drugs with Pharmacological Biological or Therapeutical Activity
Springer Berlin Germany 19771-22
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
Evaluation of Plants with Reference to the Malagasy Flora Monograph from the
IFS-NAPRECA Workshop on Bioassays Madagascar 1993 35ndash 43
Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
from Candidate Drug Selection to Commercial Dosage Form Boca Raton CRC
Press ISBN 1-57491-120-1
Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
for Conservation of Nature (IUCN) Gland 1994 Pp 50
Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
Food Chem 2003 51 375-382
Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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Jones RT Pharmaceutical Capsules 2nd edition Pharmaceutical Press London
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Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
conservation Traffic EuropeInternational Cambridge 1998 UK
Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mahrotra S Rawat A Singh HK Shome U Ethanobotany 1995 7(1amp2)1-15
Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
Phytosciences In Ahmad I Aqil F Owais M (eds) Modern Phytomedicine
Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
ethnobotany In Shrivastava MM Sanghi R (Eds) Chemistry for Green
Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
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WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
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WHO National policy on traditional medicine and regulation of herbal medicines
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WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
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Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
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Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
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Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
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Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
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[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
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Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
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derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 180
monograph The sample of crude drug was also authenticated by University Institute
of Pharmacy Pandit Ravishankar Shukla University Raipur All the reagents and
solvents used were of analytical grade The ash values extractive values with various
reagents and were determined as per the WHO guidelines Three batches of
Shringyadi churna designated as SC-I SC-II and SC-III were prepared in laboratory
using method described in Ayurvedic Formulary of India Evaluation of organoleptic
characters of raw materials Pistacia integerrima (karkatasringi) Piper longum
(pippali) and Aconitum palmatum (ativisa) were performed and characters are
recorded
Laboratory batches of Shringyadi churna (SC-I SC-II and SC-III) and one marketed
preparations were also evaluated for organoleptic characters The results for the
marketed formulations M I and Laboratory formulation are found comparable
The moisture content of formulation was within acceptable range that is 224plusmn0242
and 232plusmn0282 for lab and marketed formulations respectively thus implying that the
formulation can be stored for a long period and would not easily be attacked by
microbes Physical properties namely tapped density bulk density angle of repose
hausner ratio and carrrsquos index were calculated for Lab formulation marketed
formulation and its raw materials The value of angle of repose for raw materials
Pistacia integerrima Piper longum Aconitum palmatum lab formulation (SC-I) and
marketed formulation were 2434 3128 2986 2686 and 2542 respectively which
shows good flow properties of prepared lab formulation The flow properties of lab
(SC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and Carrrsquos
index it was found 125 20 and 123 19 respectively and indicates good flow
characteristics
Seven phytochemical groups namely carbohydrate glycosides tannins flavonoids
fixed oil and proteins were detected in the ethanolic extract of lab and marketed
formulations however the aqueous extracts of both formulations shows the presence
of saponins with previously stated seven phytochemical groups Steroids were absent
in all the ingredients and formulations for both methods of extraction Results also
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 194
Addae-Mensah I 1992 Towards a Rational Scientific Basis for Herbal Medicine
ndash A phytochemistrsquos two-decade contribution Accra Ghana Universities Press
Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
B Aryavidyan 1998 11(3)164-67
Alam M Dasan KKS Rukmani B Purshothaman KK Bull Med Ethnobot Res
1985 6(2-4)133-40
Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
Res 1983 4(3-4)158-61
Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
Ministry of Health and Family Welfare Department of Indian Systems of
Medicine and Homoeopathy New Delhi India
Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Bagul MS Rajani M Ind drugs 2005 42(1) 15-19
Bartram T 1995 Encyclopaedia of Herbal Medicine Grace Dorset
Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
Rockville 1995 Pp 165-178
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200414(4)207-13
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
Anal 2005 37937- 41
Ellenberger A First International Symposium on the Conservation of Medicinal
Plants in Trade in Europe TRAFFIC Europe Kew 1998 UK
Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
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for Medicinal Products for Veterinary Use (CVMP) London UK
Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
proprietary medicinal products Off J 1965 22 369ndash373
Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
Farnsworth NR Bingel AS In Wagner H Wolff P (eds) New Natural Products
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
Evaluation of Plants with Reference to the Malagasy Flora Monograph from the
IFS-NAPRECA Workshop on Bioassays Madagascar 1993 35ndash 43
Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
from Candidate Drug Selection to Commercial Dosage Form Boca Raton CRC
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
for Conservation of Nature (IUCN) Gland 1994 Pp 50
Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
Food Chem 2003 51 375-382
Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
conservation Traffic EuropeInternational Cambridge 1998 UK
Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mahrotra S Rawat A Singh HK Shome U Ethanobotany 1995 7(1amp2)1-15
Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
Phytosciences In Ahmad I Aqil F Owais M (eds) Modern Phytomedicine
Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
ethnobotany In Shrivastava MM Sanghi R (Eds) Chemistry for Green
Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
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Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
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Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
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1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
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17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
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Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
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56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
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especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
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national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
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66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 181
confirm that both formulations are more soluble in ethanol than water It depicts that
constituents present in formulations are more soluble in ethanol
Total ash value of Pistacia integerrima Piper longum Aconitum palmatum lab
formulation and marketed formulation were 5032 plusmn 0624 2981 plusmn0243 4621
plusmn0334 7224 plusmn 0247 and 19633 plusmn 0552 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of lab (SC-I) and marketed formulation were
found 3446 plusmn 0268 and 5041 plusmn 0368 respectively shows that a small amount of the
inorganic component is insoluble in acid it indicates adulteration of raw ingredients
by substance like silica rice husk is very less in both formulation Low acid-insoluble
ash value may also affect amount of the component absorbed in the gastrointestinal
canal when taken orally
Alcohol-soluble extractive values were found 38486plusmn1842 and 31824plusmn0251 for lab
and marketed formulation respectively which is higher than water soluble extractive
value of both formulations Higher ethanol-soluble extractive value implies that
ethanol is a better solvent of extraction for the formulation than water
Spectrophotometric analysis
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Shringyadi churna and
powder of Piper longum (Pippali) was carried out separately The concentration of
piperine content in raw material was found to be 1852 plusmn 0241 ww in Piper longum
The content of piperine in different batches of Shringyadi churna was found to be
0605 plusmn 0 001 0599 plusmn 0127 0602 plusmn 0008 and 0535 plusmn 0015 ww
respectively for lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively Recovery studies are indicative of reproducibility of method Hence the
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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ndash A phytochemistrsquos two-decade contribution Accra Ghana Universities Press
Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
Ministry of Health and Family Welfare Department of Indian Systems of
Medicine and Homoeopathy New Delhi India
Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Bagul MS Rajani M Ind drugs 2005 42(1) 15-19
Bartram T 1995 Encyclopaedia of Herbal Medicine Grace Dorset
Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200414(4)207-13
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
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Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
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Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
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Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
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Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
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Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
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Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
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Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
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Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
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Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
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Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
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The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
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WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q3
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Q5
Q6
Q7
Q8
Q9
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 182
present method is simple sensitive precise and accurate and can be adopted for
routine quality control of Shringyadi churna
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Shringyadi churna by
simple high-performance liquid chromatography (HPLC) determination using
piperine as a standard which are important and major content in formulation RP-
HPLC methods for simultaneous determination of piperine have been developed A
C 18 LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient
mode with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The content of piperine
was found to be 1852 plusmn 0001 0605 plusmn 0012 0599 plusmn 0119 0602 plusmn 0106 and 0535
plusmn 0549 ww respectively for piper longum lab formulation (SC-I SC-II SC-III)
and marketed formulation (MF) respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Shringyadi churna using piperine as a standard is
developed The piperine is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of piperine in
different batches of Shringyadi churna was found to be 1920 plusmn 0082 0624 plusmn 0005
0618 plusmn 0046 0614 plusmn 0032 and 0569 plusmn 0225 ww respectively for piper
longum lab formulation (SC-I SC-II SC-III) and marketed formulation (MF)
respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of piperine in formulations These findings can be used as routine
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Shringyadi churna
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
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Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
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Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
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Choudhary B Current Sci 2002 83 366ndash369
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
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Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
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Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
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Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
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Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
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Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
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Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
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Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
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Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
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Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
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Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
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Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
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Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
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Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
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Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
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The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 183
Stability studies
During accelerated stability studies physicochemical parameters as per WHO (1998)
viz colour odour taste moisture content and piperine content are studied The result
of study reveals that there are no or little observable changes in the parameters during
a time period of 6 months It indicates that the formulations are stable under the
different stability studies parameters
53 Thirikadu choornam
Thirikadu choornam is well known Siddha Formulation comprised of the fruits of
two medicinal important plants Piper longum (Pippali) Piper nigrum (Marica) and
rhizomes of Zingiber officinale (Saunth) Thirikadu choornam is a digestive tonic for
the assimilation of other foods in the body It is also used as a rejuvenator and
stimulant Thirikadu choornam plays an essential role in the treatment of a wide
variety of conditions
Thirikadu choornam three batch namely TC-I TC-II TC-III were prepared in
laboratory according to method described in Siddha Pharmacopoeia
Evaluation of organoleptic characters of powdered raw material (Piper longum Piper
nigrum and Zingiber officinale) was performed and characters are recorded
Laboratory batches of Thirikadu choornam (TC-I TC-II and TC-III) and one
marketed preparations were also evaluated for organoleptic characters The results for
the marketed formulation and Laboratory formulation were found comparable
The value of angle of repose for raw materials Piper longum (Pippali) Piper nigrum
(Marica) Zingiber officinale (Saunth) lab formulation (TC-I) and marketed
formulation were 2534 2543 2668 2661 (TC-I) 2354 and 2647 respectively
which shows good flow properties of prepared lab formulation The flow properties
of lab (TC-I) and marketed formulations were also confirmed by Hausnerrsquos ratio and
Carrrsquos index it was found 120 1695 and 129 2241 respectively and indicates
good flow characteristics
The amount of moisture in the crude drugs should be minimized in order to prevent
decomposition of either due to chemical changes or due to microbial contamination
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
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Ellenberger A First International Symposium on the Conservation of Medicinal
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Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
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Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
Farnsworth NR Bingel AS In Wagner H Wolff P (eds) New Natural Products
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
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Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
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Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
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Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
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Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
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[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
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8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 184
The percent moisture content for TC-I TC-II and TC-III are 282plusmn0124 293plusmn0442
and 276plusmn0125 while it is 293plusmn0323 for MF The moisture content of formulation
was within acceptable range (lt8) thus implying that the formulation can be stored
for a long period and would not easily be attacked by microbes The percent of
foreign matter was found to be 129plusmn0084 108plusmn0129 and 146plusmn0125 for PL (Piper
longum) PN (Piper nigrum) ZO (Zingiber officinalis) respectively Laboratory
formulations of Thirikadu choornam were prepared after removal of foreign matter
In examination no poisonous dangerous and harmful foreign matter or residue was
found
Total ash value of PL (Piper longum) PN (Piper nigrum) ZO (Zingiber officinalis)
lab formulation (TC-I) and marketed formulation were 3281 plusmn 0548 4469 plusmn 0276
5237 plusmn 0342 4232 plusmn 0321 and 5235 plusmn 0732 respectively The value of total ash in
marketed formulation is comparatively high in comparison to lab formulation may be
because of the higher amounts of inorganic components present in marketed
formulation Acid-insoluble ash value of prepared lab formulations (TC-I) and
marketed formulation were 0681 plusmn 0043 and 0636 plusmn 0056 respectively shows that a
small amount of the inorganic component is insoluble in acid it indicates adulteration
of raw ingredients by substance like silica rice husk is very less in both formulation
Low acid-insoluble ash value may also affect amount of the component absorbed in
the gastrointestinal canal when taken orally
Alcohol-soluble and water soluble extractive values of lab and marketed formulation
were 39478plusmn1546 and 31014plusmn0321 respectively which is higher than water soluble
extractive value of both formulations Higher ethanol-soluble extractive value implies
that ethanol is a better solvent of extraction for the formulation than water
The presence of different constituents in the Thirikadu choornam and its raw
materials is detected by their phytochemical analysis The formulations are found to
contain alkaloids carbohydrates volatile oil resin saponins and proteins The same
constituents are present in marketed preparations
Spectrophotometric analysis
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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ndash A phytochemistrsquos two-decade contribution Accra Ghana Universities Press
Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
B Aryavidyan 1998 11(3)164-67
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1985 6(2-4)133-40
Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
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Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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Medicine and Homoeopathy New Delhi India
Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Bagul MS Rajani M Ind drugs 2005 42(1) 15-19
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
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Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
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Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
proprietary medicinal products Off J 1965 22 369ndash373
Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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and Plant Drugs with Pharmacological Biological or Therapeutical Activity
Springer Berlin Germany 19771-22
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
Evaluation of Plants with Reference to the Malagasy Flora Monograph from the
IFS-NAPRECA Workshop on Bioassays Madagascar 1993 35ndash 43
Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
from Candidate Drug Selection to Commercial Dosage Form Boca Raton CRC
Press ISBN 1-57491-120-1
Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
for Conservation of Nature (IUCN) Gland 1994 Pp 50
Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
Food Chem 2003 51 375-382
Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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Jones RT Pharmaceutical Capsules 2nd edition Pharmaceutical Press London
2004 18-23
Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
conservation Traffic EuropeInternational Cambridge 1998 UK
Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mahrotra S Rawat A Singh HK Shome U Ethanobotany 1995 7(1amp2)1-15
Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
Phytosciences In Ahmad I Aqil F Owais M (eds) Modern Phytomedicine
Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
ethnobotany In Shrivastava MM Sanghi R (Eds) Chemistry for Green
Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
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Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
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31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
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national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
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69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 185
The spectrophotometric determination of formulations was carried out through UV
spectrophotometer at 3425 nm for piperine The absorbance characteristics show that
piperine follow Beer Lambertrsquos law within the concentration range 2-10 microgml at the
λ-max of 3425 nm The estimation of piperine content of the Thirikadu choornam
Piper longum (Pippali) and Piper nigrum (Marica) was carried out separately The
concentration of piperine content in raw material was found to be 1852 plusmn 0241 ww
in Piper longum and 3685 plusmn 0164 The content of piperine in different batches of
Thirikadu choornam was found to be 1829 plusmn 0 011 1823 plusmn 0145 1826 plusmn 0123
and 1635 plusmn 0156 ww respectively for lab formulation (TC-I TC-II and TC-III)
and marketed formulation (MF) respectively Recovery studies are indicative of
reproducibility of method Hence the present method is simple sensitive precise and
accurate and can be adopted for routine quality control of Thirikadu choornam
HPLC fingerprinting method
With a view to develop the fingerprint method for Thirikadu choornam simple high-
performance liquid chromatography (HPLC) determination using piperine as a
standard was performed RP- HPLC methods for determination of Piperine from the
fruits of Pippali Marica and Thirikadu choornam have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 3425 nm Validation of the method was done with a view to
demonstrate its selectivity linearity precision and accuracy The piperine is the chief
constituent of the Thirikadu choornam and two of its component of fruits of Piper
longum (Pippali) Piper nigrum (Marica) The concentration of piperine present in
raw materials is found to be 3685 plusmn 0164 ww in Piper nigrum and 1852 plusmn 0001
ww in Piper longum respectively and in three identical laboratory batch of Thirikadu
choornam name TC-I TC-II and TC-III and marketed formulation were 1841 plusmn
0005 1837 plusmn 0009 1832 plusmn 0111 and 1645 plusmn 0741 ww respectively The
HPLC method developed for the estimation of piperine was validated by statistical
analysis and recovery studies
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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ndash A phytochemistrsquos two-decade contribution Accra Ghana Universities Press
Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
B Aryavidyan 1998 11(3)164-67
Alam M Dasan KKS Rukmani B Purshothaman KK Bull Med Ethnobot Res
1985 6(2-4)133-40
Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
Ministry of Health and Family Welfare Department of Indian Systems of
Medicine and Homoeopathy New Delhi India
Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Bagul MS Rajani M Ind drugs 2005 42(1) 15-19
Bartram T 1995 Encyclopaedia of Herbal Medicine Grace Dorset
Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
Rockville 1995 Pp 165-178
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200414(4)207-13
Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
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Ellenberger A First International Symposium on the Conservation of Medicinal
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Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
criteria for herbal substances herbal preparations and herbal medicinal
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for Medicinal Products for Veterinary Use (CVMP) London UK
Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
proprietary medicinal products Off J 1965 22 369ndash373
Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
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IFS-NAPRECA Workshop on Bioassays Madagascar 1993 35ndash 43
Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
from Candidate Drug Selection to Commercial Dosage Form Boca Raton CRC
Press ISBN 1-57491-120-1
Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
for Conservation of Nature (IUCN) Gland 1994 Pp 50
Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
Food Chem 2003 51 375-382
Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
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Jones RT Pharmaceutical Capsules 2nd edition Pharmaceutical Press London
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
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Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
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Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mahrotra S Rawat A Singh HK Shome U Ethanobotany 1995 7(1amp2)1-15
Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
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Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
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Mukherjee PK 2005 Exploring green resources for drug development through
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
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Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
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WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
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[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
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[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
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631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 186
HPTLC fingerprinting method
To develop the solvent system samples were run in different solvent Better results
are obtained with mobile phase consisting toluene ethyl acetate (7030vv) On the
basis of TLC profile HPTLC study is performed HPTLC fingerprint method is
developed for Thirikadu choornam using piperine as a standard which is an
important and major content of formulation HPTLC methods for determination of
piperine from the Thirikadu choornam along with its raw materials have been
developed The method was validated for linearity accuracy limit of detection limit
of quantification inter-day and intra - day assay precision repeatability of
measurement and repeatability of sample application The concentration of piperine
present in raw materials is found to be 3699 plusmn 0064 ww in Piper nigrum and 1889
plusmn 0011 ww in Piper longum respectively and in three identical laboratory batch of
Thirikadu choornam name TC-I TC-II and TC-III and marketed formulation were
1852 plusmn 0005 1843 plusmn 0009 1831 plusmn 0121 and 1639 plusmn 0852 ww respectively
The HPTLC method developed is simple accurate and the statistical analysis proved
that the method is reproducible and efficient for the analysis of piperine
Stability studies
Accelerated stability studies were performed on the basis of physicochemical
parameters viz colour odour taste moisture content volatile oil content and piperine
content Through out the duration of study little or insignificant observable changes
are recorded and the formulations found stable for the length of time of study ie 6
months
54 Standardization of Safoof-E-Sana
Tibb-e-Unani (Unani medicine) claims to possess many safe and effective drugs
useful in various abdominal disorders The formulations despite being widely used in
the management of abdominal ailments have not been scientifically studied for their
pharmacological effects and physicochemical evaluation for assurance of uniformity
of the quality of formulations
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
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Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
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Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
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Ellenberger A First International Symposium on the Conservation of Medicinal
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EMEA 2005 Guideline on specifications Test procedures and acceptance
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Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
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Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
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Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
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Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
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Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
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Raina MK Indian J Nat Prod 1993 918-22
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Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
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Remirez DC J Compl Int Med 2006 3(1) Article 3
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Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
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95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
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Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
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Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
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Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
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Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
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Wallis TE Text book of Pharmacognosy 5th
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WHO Essential drugs and medicines policy httpwwwwhoInt
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WHO Expert Committee on Specifications for Pharmaceutical Preparations
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WHO National policy on traditional medicine and regulation of herbal medicines
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WHO Regulatory situation of herbal medicines a Worldwide Review
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q16
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Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 187
Safoof-E-Sana is a fine powder form (Unani Formulation) which is widely used as
laxative at dose of 3-6 gmday It is composed of Burge Sana (Senna leaves) used in
constipation fever skin diseases and gout Zanjabeel (dry ginger) used in asthma
diarrhea cardiac diseases and wounds Poste Haleel e zard (haritakee) used in cardiac
diseases jaundice cough and carcinoma and Namak e Siyah (balck salt) claims to
posses laxative and carminative The key ingredient of Safoof-E-Sana is senna leaves
(Cassia angustifolia) All the ingredients are firstly powdered separately and mixed
together The genus senna is known to possess important medicinal properties as it is
a rich source of anthraquinones flavonoids polysaccharides sterols and stilbenoids
showing a wide spectrum of biological activity From the therapeutical point of view
the most important characteristics is the laxative property The biological activity is
related to the contents of anthraquinones and flavonoids in this genus
Three batches of Safoof-E-Sana designated as SS-I SS-II and SS-III were prepared
in laboratory using method described in Unani Pharmacopoeia These three batches of
lab formulation and one marketed preparation were evaluated for organoleptic
characters The results for the marketed formulations M I and Laboratory formulation
are found comparable
The moisture content of Zingiber officinale Cassia angustifolia Terminalia chebula
lab formulation (SS-I) and marketed formulation were found 313plusmn0682 334plusmn0445
382plusmn0474 325plusmn0582 and 393plusmn0323 ww respectively The moisture content of
formulation was within acceptable range (lt8) thus implying that the formulation
can be stored for a long period and would not easily be attacked by microbes
Physical properties namely tapped density bulk density angle of repose hausner
ratio and carrrsquos index were calculated for Safoof-E-Sana and its raw materials The
value of angle of repose for raw materials Zingiber officinale Cassia angustifolia
Terminalia chebula Balck salt lab formulation (SS-I) and marketed formulation
were 3448 2952 2892 2254 2768 and 2668 respectively which shows good flow
properties of prepared lab formulation The flow properties are also confirmed by
Hausnerrsquos ratio and Carrrsquos index Values of Hausnerrsquos ratio less than 125 indicate
good flow (20 Carr Index) and the value greater then 125 indicates poor flow (33
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Addae-Mensah I 1992 Towards a Rational Scientific Basis for Herbal Medicine
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Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
Association of the European Self-Medication Industry (AESGP) 1998
Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
B Aryavidyan 1998 11(3)164-67
Alam M Dasan KKS Rukmani B Purshothaman KK Bull Med Ethnobot Res
1985 6(2-4)133-40
Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
Balasubramanian M J Res Ayur Siddha 1982 3(3-4)200-04
Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Bartram T 1995 Encyclopaedia of Herbal Medicine Grace Dorset
Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
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Ernst E Am J Med 1998 104 170-178
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
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Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
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Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
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Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
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Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
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Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
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Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
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Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
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Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
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Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
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The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
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26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
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31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 188
Carr Index) The flow properties of lab (SS-I) and marketed formulations were also
confirmed by Hausnerrsquos ratio and Carrrsquos index it was found 123 19 and 127 2115
respectively and indicates good flow characteristics
One notable difference as a result of the methods of extraction is the possibility that
the alkaloids in Cassia angustifolia are more water soluble the reason why the
presence of that group was not detectable in the ethanolic extract Furthermore where
more than one test was conducted for the detection of a chemical group such as the
alkaloids no differences in the results were observed for the different tests Out of the
nine phytochemical groups investigated five namely carbohydrate glycosides
tannins and proteins were detected in the ethanolic extract of lab formulation and
seven were present in the aqueous extract of lab formulation including alkaloids and
saponins with previously stated five Fixed oil and steroids were absent in all the
ingredients and lab formulation for both methods of extraction
Total ash value of Zingiber officinale Cassia angustifolia Terminalia chebula lab
formulation (SS-I) and marketed formulation were 5023plusmn 0643 7023 plusmn 0426
3891 plusmn0423 19146plusmn0237 and 20223plusmn0336 respectively The value of total ash in
formulation is comparatively high because of the presence of black salt in
formulation Acid-insoluble ash value of lab formulation (SS-I) and marketed
formulation were 2351plusmn0223 and 2541 plusmn 0056 which shows that a very small
amount of the inorganic component is insoluble in acid it indicates adulteration of
raw ingredients by substance like silica rice husk is very less
Higher water-soluble extractive value of lab and marketed preparation (45784plusmn0876
and 40147plusmn1654 respectively) implies that water is a better solvent of extraction for
the formulation than ethanol
Spectrophotometric analysis
Safoof-E-Sana and Terminalia chebula is estimated spectrophotometrically for its
gallic acid content against standard gallic acid solution on UV-Visible
Spectrophotometer at λmax 271 nm The concentration of gallic acid present in
Terminalia chebula was 2952 plusmn 0 124 ww and in three identical laboratory batch
of Safoof-E-Sana SS-I SS-II and SS-III it was found to be 0704 plusmn 0 012 0699 plusmn
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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ethnobotany In Shrivastava MM Sanghi R (Eds) Chemistry for Green
Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 201
Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
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WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
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WHO National policy on traditional medicine and regulation of herbal medicines
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WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
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Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
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Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
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MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
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Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
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[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
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derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 189
0114 and 0702 plusmn 0123 ww respectively In marketed formulation the gallic acid
content was found 0612plusmn0151 ww The method was validated statistically The
gallic acid content of all the three batches is found to be in close proximities with
each other and recovery studies are indicative of reproducibility of method The
results were comparable to marketed formulations Hence the present method is
simple and accurate and can be adopted for routine quality control of Safoof-E-Sana
HPLC fingerprinting method
The study is an attempt to develop the fingerprint method for Safoof-E-Sana by
simple high-performance liquid chromatography (HPLC) determination using gallic
acid as a standard which are important and major content in formulation RP- HPLC
methods for simultaneous determination of gallic acid have been developed A C 18
LUNA (5 micron 25 cmtimes46 mm) column from Phenomenex in binary gradient mode
with mobile phase methanol at flow rate is 10mlmin used and effluent was
monitored at 271 nm Validation of the method was done with a view to demonstrate
its selectivity linearity precision and accuracy The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana lab formulations (SS-I SS-II
SS-III) and marketed formulation were found to be 3145plusmn0013 0735 plusmn 0012
0738 plusmn 0016 0730 plusmn 0015 0646 plusmn 0062 ww respectively
HPTLC fingerprinting method
HPTLC fingerprint method for Safoof-E-Sana using gallic acid as a standard is
developed The gallic acid is an important content in the formulation and all of its
herbal raw ingredients The method was validated for linearity accuracy limit of
detection limit of quantification inter-day and intra-day assay precision repeatability
of measurement and repeatability of sample application The content of gallic acid in
Terminalia chebula different batches of Safoof-E-Sana (SS-I SS-II SS-III) and
marketed formulation were found 3152 plusmn 0002 0739 plusmn 0011 0738 plusmn 0018 0733
plusmn 0011 and 0649 plusmn 0022 ww respectively
The statistical analysis proved that the method is reproducible and efficient for the
analysis of gallic acid in formulations These findings can be used as routine
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Dasan KKS Sathiavasan K Purshothaman KK Bull Med Ethnobot
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
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Alderborn G Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 398
Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Artuso A Pharmaceutical Products Press 1997 New York
Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
Ayurvedic Pharmacopoeia of India Part I Vol I 2001 Government of India
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Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
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Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
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Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
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Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200340(6)333-39
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
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Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
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56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
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Mukherjee PK Drug Info Journal 2001 35 631ndash640
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Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
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Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
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Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
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Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
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Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
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Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
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Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
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Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
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Wallis TE Text book of Pharmacognosy 5th
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WHO National policy on traditional medicine and regulation of herbal medicines
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WHO Regulatory situation of herbal medicines a Worldwide Review
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Other uses including reproduction and distribution or selling orlicensing copies or posting to personal institutional or third party
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regarding Elsevierrsquos archiving and manuscript policies areencouraged to visit
httpwwwelseviercomcopyright
Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q16
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Q19
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 190
chromatographic fingerprinting method for the standardization of the herbal raw
materials as well as the finished formulation of Safoof-E-Sana
Stability studies
In the accelerated stability studies physicochemical parameters as per Who (1998)
viz colour odour taste moisture content and gallic acid content were studied The
result of study reveals that there are no or little observable changes in the parameters
during a time period of 6 months It indicates that the formulations are stable under
the different stability studies parameters
55 Development of Modern dosage form (Capsule) of selected Indigenous
formulations
In present study we have taken four traditional medicines and all are in powder
(churna) form We have developed the capsule dosage form for these four
formulations to increase their dose accuracy stability convenience to handle and
over and all to improve their global acceptance All the selected indigenous
formulations have the dose of 500 to 1000 mgday as per their official formularies
Hence they are very much suitable to be developed as capsule dosage form The size
of the capsule shell was selected Zero ldquo0rdquo as this size have the reported filling
capacity between 500-600 mg
Uniformity of weight
Uniformity of weight were determined for the each selected formulations as per the
method described above The capsules produced were physically elegant and
acceptable and met the pharmacopoeia specifications for content and weight
uniformity (The average deviation in weight were 0081plusmn0093 0108plusmn0093
0115plusmn0117 and 0246plusmn0143 respectively for BC (Balacaturbhadrika churna) SC
(Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) Results
shows that all the capsule formulations complies with the Indian Pharmacopoeia
range (lt75)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
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Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Ayensu ES DeFilipps RA Smithsonian Institution 1978 Washington DC
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Bagul MS Rajani M Ind drugs 2005 42(1)15-19
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Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
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Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
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Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
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Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Chrubasik S Sporner F Wink M Forsch Komplementar med 1996357ndash63
Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
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Ellenberger A First International Symposium on the Conservation of Medicinal
Plants in Trade in Europe TRAFFIC Europe Kew 1998 UK
Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
criteria for herbal substances herbal preparations and herbal medicinal
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(EMEA) Committee for Medicinal Products for Human Use (CHMP) Committee
for Medicinal Products for Veterinary Use (CVMP) London UK
Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
provisions laid down by Law Regulation or Administrative Action relation to
proprietary medicinal products Off J 1965 22 369ndash373
Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
Farnsworth NR Bingel AS In Wagner H Wolff P (eds) New Natural Products
and Plant Drugs with Pharmacological Biological or Therapeutical Activity
Springer Berlin Germany 19771-22
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
Evaluation of Plants with Reference to the Malagasy Flora Monograph from the
IFS-NAPRECA Workshop on Bioassays Madagascar 1993 35ndash 43
Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
from Candidate Drug Selection to Commercial Dosage Form Boca Raton CRC
Press ISBN 1-57491-120-1
Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
Hamburger M Hostettmann K Phytochem 1991 30 3864-3874
Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
15(3)222-25
Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
edition 1966165
httpwwwmotherherbscom and httpenwikipediaorg
IUCN Guidelines on the conservation of medicinal plants International Union
for Conservation of Nature (IUCN) Gland 1994 Pp 50
Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
Food Chem 2003 51 375-382
Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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2004 18-23
Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
conservation Traffic EuropeInternational Cambridge 1998 UK
Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mahrotra S Rawat A Singh HK Shome U Ethanobotany 1995 7(1amp2)1-15
Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
Phytosciences In Ahmad I Aqil F Owais M (eds) Modern Phytomedicine
Turning Medicinal Plants into Drugs WILEY-VCH Verlag GmbH amp Co KGaA
Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
ethnobotany In Shrivastava MM Sanghi R (Eds) Chemistry for Green
Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
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Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
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Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
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69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 191
Disintegration time
Disintegration time for each selected formulations BC (Balacaturbhadrika churna)
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana) were
estimated as per Indian Pharmacopoeia Finding of disintegration time of above
mentioned formulations were 520plusmn0480 546plusmn0456 510plusmn0431and 535plusmn0009
respectively Results were in the acceptable range (lt 7 min)
Moisture content
After the capsules were filled the moisture level of its contents were tested The
results of these tests indicated that the moisture level of the contents of the each
formulations BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu
choornam) and SS (Safoof-E-Sana) were 302plusmn034 288plusmn234 270plusmn332 and
396plusmn345 respectively The entire freshly prepared capsule shows moisture content at
acceptable range (lt 8) as per WHO guidelines Since the moisture absorbed may
speed up degradation the humidity conditions during the manufacture of the capsules
can thus be a crucial factor and these capsules should preferably be manufactured
under more tightly controlled humidity conditions
Stability studies
Following storage conditions were selected as per ICH guidelines which are long
term storage condition (25degC60 relative humidity (RH) for 12 months) accelerated
conditions (40degC75 RH) for 6 months and to reveal the effect of container we were
also determined the moisture content outside the container at 25degC60 relative
humidity (RH) for 6 months
25degC60 relative humidity (RH) inside container
Results shows that at 25degC60 relative humidity (RH) inside container all the
selected lab formulations do not posses the significant moisture content which was
331plusmn055 318plusmn066 309plusmn023 and 472plusmn054 for BC (Balacaturbhadrika churna)
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
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Alderborn G Pharmaceutics the science of dosage form design 2nd edition
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Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
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Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
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Butcher SP Target discovery and validation in the postgenomic era Neurochem
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Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
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IUCN Guidelines on the conservation of medicinal plants International Union
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WHO National policy on traditional medicine and regulation of herbal medicines
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO Traditional Medicine Programme WHOEDMTRM2000
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WHO 2003 WHO guidelines on good agricultural and collection practices
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Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
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Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q23
Q24
Q25
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Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 192
SC (Shringyadi churna) TC (Thirikadu choornam) and SS (Safoof-E-Sana)
respectively Hence it reflects that in this storage condition moisture content of each
capsule was lt5 ww which indicates that there is less chances of microbial growth
and capsule will not become soft Percent active ingredient was estimated with
respect to its initial concentration present before storage in respective formulations It
was found 9888plusmn029 9789plusmn043 and 9691plusmn087 ww of piperine in BC SC and
TC respectively Similarly for SS gallic acid was found 9868plusmn022 ww with
respect to its concentration present in formulation before storage The above results
reveal that this storage condition is suitable for this developed capsule dosage form
formulations
25degC60 relative humidity (RH) outside the containers
At this condition all the formulations shows significant increase in the percent
moisture content It was 1786plusmn034 1751plusmn043 1763plusmn012 and 1888plusmn043 for BC
(Balacaturbhadrika churna) SC (Shringyadi churna) TC (Thirikadu choornam) and
SS (Safoof-E-Sana) respectively Results at this condition reflect that powder is
hygroscopic in nature and it should be kept inside the container immediately after the
formulation Percent active ingredient was estimated with respect to its initial
concentration present before storage in respective formulations It was found
9120plusmn041 9062plusmn034 and 8948plusmn073 ww of piperine in BC SC and TC
respectively Similarly for SS gallic acid was found 9222plusmn028 ww with respect to
its concentration present in formulation before storage The above results depict
significant loss of active ingredients in formulations
40ordmC75 relative humidity (RH) inside containers
This condition reveals that even inside the container storage of the capsule in
atmospheres of high humidity will increase the moisture content which typically
accelerates decompositions that result from hydrolysis Also an increase in
temperature causes an increase in the rate of chemical reaction The results at this
condition shows percent moisture content 884plusmn012 867plusmn032 850plusmn087 and
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
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[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
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631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
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6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
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Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
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Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Summary and Conclusion
Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations 193
1003plusmn012 for BC (Balacaturbhadrika churna) SC (Shringyadi churna) TC
(Thirikadu choornam) and SS (Safoof-E-Sana) respectively Percent active ingredient
was estimated with respect to its initial concentration present before storage in
respective formulations It was found 9363plusmn011 9228plusmn085 and 9061plusmn032 ww
of piperine in BC SC and TC respectively Similarly for SS gallic acid was found
9111plusmn048 ww with respect to its concentration present in formulation before
storage The above result again shows significant loss of active ingredients in
comparison with 25degC60 relative humidity (RH) inside container storage
condition
Through these studies we can conclude that the capsule of each selected lab
formulations passed the test for uniformity of weight All capsules disintegrated
within 7 minutes Moisture content of capsule was lt5 ww at 25degC60 relative
humidity (RH) inside container which indicates that there is less chances of microbial
growth and capsule will not become soft and most important at this storage condition
(25degC60 relative humidity (RH) inside container) the amount of active ingredients
was also found comparable with fresh formulation
The present research work establishes the organoleptic physicochemical
phytochemical and fingerprinting aspects of selected traditional indigenous
formulations The above established quality control parameters ensures the quality
safety and efficacy of selected formulations and hence their global acceptance This
work also gives guidelines for the standardization of other indigenous formulations
with the help of standard marker compounds On the other hand development of
modern dosage forms like capsule increase their dose accuracy stability convenience
to handle and worldwide recognition
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[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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Addae-Mensah I 1992 Towards a Rational Scientific Basis for Herbal Medicine
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Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The
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Agrawal RG Joshi PC Pandey MJ Pandey G Ancient Sci Life 1996 15(3)169-
71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Alam M Rukmani B Meenakshi N Dasan KKS Bhima Rao R J Res Ayur
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Alam M Sathiavasan K Varadarajan TV Shanmugadhasan KK Purshothaman
KKA J Res Ayur Siddha 19823(3-4)216-20
Alderborn G Pharmaceutics the science of dosage form design 2nd edition
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Anand KA Thirugunana sambanatham P Rajendran V Muralidharan R
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Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
MBP Santos DS Mem Inst Oswaldo Cruz Rio de Janeiro 2005 100(6) 575-606
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Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
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Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
Dutta SK International Seminar-Traditional Medicine Calcutta 1992 69-70
Dwivedi AK Chaudhary M Kulshreshtha DK Sarin JPS J Res Ayur amp Siddha
1991 12(1-2)85-92
Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
Eapen Saumy MS Grampurohit ND Ind drugs 2002 39(2)101-05
Elamthuruthy AT Shah CR Khan TA Tatke PA Gabhe YS J Pharm Biomed
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Ellenberger A First International Symposium on the Conservation of Medicinal
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Ellenberger A TRAFFIC Europe Kew UK 1998 Pp 127-130
EMEA 2005 Guideline on specifications Test procedures and acceptance
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Ernst E Am J Med 1998 104 170-178
European Commission Council Directive 6565EEC on the approximation of
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Fabricant D Farnsworth NR Env Health Perspec 2001 109 63-75
Farnsworth NR Bingel AS In Wagner H Wolff P (eds) New Natural Products
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Farnsworth NR In Rasoanaivo P Ratsimamanga-Urverg S (eds) Biological
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Farnsworth NR J Pharm Sci 1996 55 225-276
Francis M Sane RT and Tipins S Ind Drugs 2003 40(12) 712-715
Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
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Heide L Phytother Res 1991 121-8
Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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Ibanez E Kubatova A Senorans FJ Cavero S Reglero G Hawthorne SB J Agric
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Jain UK Dixit VK Ind drugs 200340(6)333-39
Jain UK Dixit VK Ind drugs 200441(8) 469-72
Jain V Saraf S Saraf S Asian J Chem 2007 19 (2) 1406-1409
Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
Jain V Vyas A Saraf S Saraf S Asian J Res Chem 2011 4 (2) 183-186
Jain V Vyas A Saraf S Saraf S Res J Pharm Tech 2011 4 (2) 230-233
Johnston PA Johnston PA Drug Discov Today 2002 7 353-363
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Kasar R Laddha KS Chaudhary J Shukla A Nat Prod Radiance 2006 5(1)33-
41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
Medicine Calcutta1992 69-76
Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
318563ndash64
Kenakin T Nat Rev Drug Discov 2003 2 429-438
Kicklighter CE Kubanek J Barsby T Hay ME Mar Ecol Prog Ser 2003 263
299-306
Kinghorn AD Biotechnology 1994 2681-108
Knowles J Gromo G Nat Rev Drug Discov 2003 2 63-69
Kokate CK Practical Pharmacognosy New Delhi Vallabh Prakashan 1994107-
113
Kufer J Forther H Poll E Heinrich M J Pharmacy Pharmacol 2005 571127-
1152
Kursar TA Capson TL Coley PD Corley DG Gupta MB Harrison LA Ortega-
Barriacutea E Windsor DM Pharmaceutical Biol 1999 37 S114-S126
Lalla JK Hamrapurkar PD Mamania HM Indian Drugs 2001 38(2)87-94
Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lewis WH Elvin-Lewis MP Ann Mo Bot Gard 1995 82 16-24
Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mendonca-Filho RR 2006 Bioactive Phytocompounds New Approaches in the
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Weinheim
Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
Morris BA Can Med Assoc J 1989 141 875-876
Mukherjee PK Saha K Perumal P Pal SK Saha BP J Scie Ind Res
199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
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Environment Narosa Publishing House New Delhi India pp 287ndash299
Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
Nahata A Dixit VK Ind J Pharm Sci 200870(6) 834-837
Nair KV Nair AR Nair CPR Bulletin of Medico-Ethnobotanical Research 1997
18(3-4)151-56
Newall CA Anderson LA Phillipsen DJ The Pharmaceutical Press London
1996296
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
Pandey NN Yadav RS Sharma GK Sachitra Ayurved 199749(12)937-40
Pandey RK Saraf S Saraf S Biosci Biotech Res Asia 2009 6(1) 210-212
Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
Phillipson JD Anderson LA J Ethnopharmacol 1989 25 61-72
Pillai NK 1998 History of Siddha medicine Department of Indian Medicine and
Homeopathy Chennai India pp 33ndash35
Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
Ootacamund1995 A44
Raina MK Indian J Nat Prod 1993 918-22
Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
Roman M 2001 The benefits and pitfalls of standardizing botanicals extracts
Natural Products Insider
Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
Altern med 20063(2)27-36
Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
1998a 19(3-4)165-75
Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
Ethnopharmacol 2006104(1-2)113-18
References
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Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
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[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
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8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
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57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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71
Ahmad M Khan MA Zafar M Sultana S Afr J Trad CAM 2007 4 (1) 112- 120
Ajazuddin Saraf S Fitoterapia (Elsevier) 2010 81(7)680ndash689
Ajazuddin Saraf S Pharmacog Rev 2012 (Article in Press)
Alam M Sarawathy VN Venugopalan TN Jaya N Namboodiri PKN Ramarao
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Basso LA Pereira da Silva LH Fett-Neto AG Filgueira de Azevedo Junior W de
Souza Moreira I Palma MS Calixto JB Filho SA Ribeiro dos Santos R Soares
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Berry JP McFerren MA Rodriguez E Phytochemicals and Health ASPP
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
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Bhagwat M Kashalkar RV Bhave AS Vaidya SS Ramaswami V Ind Drugs
200441(1)12-18
Bhavsar GC Pundrikakshudu K Kudalkar VP Patel RK Ind J Nat Prod
200120(1)33-35
Bhutani KK Gupta DK Kapil RS Update Ayurveda-94 Bombay India 1994
52-63
Biringanine G Chiarelli MT Faes M Duez P Talanta 2006 69(2) 418-424
Bleicher KH Bohm HJ Muller K Alanine AI Nat Rev Drug Discov 2003 2
369-378
Bodekar G Kronenberg F Am J Public Health 2002921582ndash91
Brijesh S Daswani PG Tetali P Rojatkar SR Antia NH Birdi TJ J Zhejiang
Univ SCIENCE B 2006 7 665-674
Butcher SP Target discovery and validation in the postgenomic era Neurochem
Res 2003 28 367-371
Cardellina JH JNatProd 2002 651073ndash84
Chanabra RS Bucher M Wolfe abd Portier C Int J Hyg Environ Health 2003
206 437-445
CHEMEXCIL 1992 Selected Medicinal Plants of India Bhartiya Vidya
Bhavans Swami Prakashanand Ayurveda Research Centre Bombay
Choudhary B Current Sci 2002 83 366ndash369
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Cragg GM Boyd MR Khanna R Kneller R Mays TD Mazan KD Newman DJ
Sausville EA Pure Appl Chem 1999 71(9) 1619-1633
Dove A Nat Biotechnol 2003 21 859-864
Drews J Drug Discov Today 2003 8 411-420
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Dwivedi PK Pandey S Jha CB Sachitra Ayur 1999 51(7)541-43
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Gibson M Pharmaceutical Preformulation and Formulation A Practical Guide
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Giri JN Sachitra Ayur 1999 51(9)672-76
Govindarajan R Singh DP Rawat AKS J Pharm Biomed Anal 2007 43527ndash32
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Hepsibah PTA Rosamma MP Prasad NBR Kumar PS Ancient Scie Life 1996
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Hoareau L Elect J Biotech 1999 2 56ndash70
Hoffman E Thin Layer Chromatography 2nd
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IUCN Guidelines on the conservation of medicinal plants International Union
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Jain UK Dixit VK Ind drugs 200441(8) 469-72
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Jain V Saraf S Saraf S Asian J Chem 200719 (7) 5331-35
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41
Katiyar CK Bittal Babu A Narayana DBA International Seminar-Traditional
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Keane FM Munn SE DuVivier AWP Taylor NF Higgins EM Brit Med J 1999
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Kenakin T Nat Rev Drug Discov 2003 2 429-438
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Lalla JK Hamrapurkar PD Patil PG Mamania HM Ind Drugs 200239(3) 152-
56
Lange D Europersquos medicinal and aromatic plants their use trade and
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Lijuan M Xuezhu Z Haiping Z Yiru G J Chromatogr B 2007 846(1-2)139-46
Lipsky MS Sharp LK J Am Board Fam Pract 2001 14 362-367
Lord GM Tagore R Cook T Gower P Pusey CD Lancet 1999 354481ndash82
Mahadevan N Subburaju T Suresh B Ind Drugs 2004 41 (1) 46-47
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Mitra A Chakraboty S Auddy B Triphati P Sen S Saha AV Mukherjee B J
Ethnopharmacog 200280147-53
Moore K Rees S J Biomol Screen 2001 6 69-74
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199655(4)286-88
Mukherjee PK 2005 Exploring green resources for drug development through
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Mukherjee PK Clin Res and Reg Affairs 2003 249ndash264
Mukherjee PK Drug Info Journal 2001 35 631ndash640
Mukherjee PK Drug Info Journal 2002b 63 635ndash644
Mukherjee PK Eastern Publishers Business Horizons Ltd New Delhi India
2002a 1ndash37
Mukherjee PK Quality control of Herbal Drugs 1st edition India Horizons
Pharmaceutical Publishers 2002 300-16
Musthaba SM Baboota S Ahmed S Ahuja A Ali J Exp Opin Drug Del 2009
6(6) 625-637
Nacif de Abreu I Mazzafera P Plant Physiol Biochem 2005 43 241-248
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Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
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Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
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Raina MK Indian J Nat Prod 1993 918-22
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Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
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1993 14(3-4)174-78
Saraswathy A Girijarani M Suganthan J Bulletin of Medico-Ethnobotanical Res
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Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
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Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
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Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
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The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
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The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
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The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
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WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
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12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
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29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
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35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
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World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
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WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
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Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
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Contents lists available at ScienceDirect
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
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World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 202
The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 203
WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
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Contents lists available at ScienceDirect
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
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23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
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26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
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29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
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32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q12
Q13
Q14
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Q16
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Q21
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
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52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
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WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
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Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
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29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q16
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Q19
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
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12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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Q23
Q24
Q25
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Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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Padiyar A Ali J Khar RK Pharma times 200030(8)35-38
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Pandey RK Saraf S Saraf S Der Pharm Lettr 2010 2 (2) 464-470
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Purohit AP Bosale PH International Seminar on Recent Trends in Pharm Sci
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Rao VN Jha CB Maheswar T Sahai M Sachitra Ayured1997 49(11)855-57
Raskin I Ribnicky DM Komarnytsky S Ilic N Poulev A Borisjuk N Brinker A
Moreno DA Ripoll C Yakoby N OrsquoNeal JM Cornwell T Pastor I Fridlender B
Trends in Biotech 2003 20522ndash531
Rastogi S Bala S Govindrajan R Shukla M Mehrotra S Indian J Pharm Sci
200466(6)753-57
Remirez DC J Compl Int Med 2006 3(1) Article 3
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Saleem AM Gopal V Rafiullah MRM Bharathidasan P Afr J Trad comp and
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Saraswathy A Girija RM Shankari R journal of research in Ayurveda amp Siddha
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Saxena RB Dholikia MV Bulletin of Medico-Ethnobotanical Res1990 11(4)84-
95
Scartezzinia P Antognonia F Raggib MA Polia F Sabbionib C J
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Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
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Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
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Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
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Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
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Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
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Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
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Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
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Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
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WHO guidelines for Formulation of National Policy on Herbal Medicines
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WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
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WHO Guidelines on good agricultural and collection practices (GACP) for
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WHO National policy on traditional medicine and regulation of herbal medicines
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Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
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Q4
Q5
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Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q19
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
References
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Formulations] 201
Sharma A Lal K Handa SS Int J Pharmacog 199230(3)205-08
Sharma GP Singh JS Raghubanshi AS Current Science 2005 88(5) 726-734
Shastry MS Dave KK De S J Res amp educ in Indian medicine 1991 10(1)31-34
Sheth A Lal K Handa SS Phytochem Anal 2000 3129-39
Shukla K Saraf S Saraf S Ind J Pharm Edu Res 2008 42 (2) 33-38
Shukla K Saraf S Saraf S Nat Prod - An Ind J 2007 3(2) 92-95
Shukla SS Saraf S Saraf S Der Pharm Lettr 2010 2(3) 8-18
Shukla SS Saraf S Saraf S J Res Educ Ind Med 2009 15(1) 25-32
Shukla SS Saraf S Saraf S Syst Rev Pharm 2011 2(1) 48-54
Siddha Pharmacopoeia Part-I Vol-I Govt of India Ministry of Health and
Family Welfare Department of AYUSH 2008 56 132 198
Siddiqui MK CCRUM New Delhi India 1996 3ndash5
Siddiqui SH Zaidi SJH Khan G Sharma HD Ind J Unani Med 1991 1(1)37-42
Singh J Ramprakash L Ind Drugs 1997 34 (6) 360-61
Sinko PJ Martinrsquos physical Pharmacy and Pharmaceutical Sciences 5 th edition
Indian edition B I publication private limited 2006555
Somanathan AR Sadanandan K Damodaran NP Anc Sci Life 1989 9(2) 54-60
Summers M Pharmaceutics the science of dosage form design 2nd edition
Churchill Livingstone 2002 360-361
Sun G Zhi X Bi K Anal Sci 2009 25(4) 529-34
Taylor JLS Rabe T McGaw LJ Jaumlger AK Stad J Plant Growth Regulation 2001
34 23ndash37
Thankamma A Radhika LG Saudamini C Ancient science of Life1995 14(4)
276-80
Thankamma A Radhika LG Saudamini C J Res Ayur and Siddha 1996 17(1-2)
98-104
The Ayurvedic Formulary of India Part I 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2003
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 202
The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 203
WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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and sharing with colleagues
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
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The Ayurvedic Formulary of India Part II 1st edition Delhi Govt of India
Ministry of Health and Family Planning Dept of Health 2000
The Ayurvedic Pharmacopoeia of India Vol I 1st edition New Delhi Ministry of
Health and Family Welfare Government of India Department of Health 1986
The Drugs and Cosmetics Act and Rules government of INDIA Ministry of
Health and Family Welfare1940 191-204
The Pharmacopoeia of India 2nd
edition Delhi Manager of publications Govt of
India 1966Appendix XXXI XXXII 971-85
Tiwari SK Pattanshetty JK Pushpalatha H J Res Ayur and Siddha 199314(1-
2)83-87
Unani Pharmacopoeia New Delhi IMPCOPS Publication 2004 137
Vaidya ADB Ind J Pharmacol 2006 38 311-315
Vasudevan H 2004 The Science Creative Quarterly
(httpwwwscqubccap=286)
Verkman AS Am J Physiol Cell Physiol 2004 286 C465-C474
Verpoorte R J Pharm Pharmacol 2000 52 253-262
Vlietinck AJ Vanden Berghe DA J Ethnopharmacol 199132 141-153
Wadekar MP Rode CV Bendale YN Patil KR Gaikwad AB Prabhune AA J
Pharm Biomed Anal 20061473-78
Wallis TE Text book of Pharmacognosy 5th
edition London J and A Churchill
Ltd 19676
Wei X Zhang S Zhai W Zhang S and Wang Z Zhongguo Zhong Yao Za Zhi
2009 34(3)304-6
WHO 2001 Legal status of traditional medicine complementaryalternative
medicine a worldwide review 2001 Geneva
WHO guidelines for Formulation of National Policy on Herbal Medicines
Alexandria 199416-36
WHO guidelines for the Assessment of Herbal MedicinesGeneva1991
WHOTRM914
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Formulations] 203
WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
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WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
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Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
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Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
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Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
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Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
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Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
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[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
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Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
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derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
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6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
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12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 203
WHO guidelines Quality Control Methods for Medicinal Plant Materials 2004
3-70
WHO Essential drugs and medicines policy httpwwwwhoInt
medicinesorganizationtrmorgtrmdefshtml August 2005
WHO Expert Committee on Specifications for Pharmaceutical Preparations
Thirty-fourth report Geneva 1996 863178-84
WHO Guidelines on good agricultural and collection practices (GACP) for
medicinal plants 2003 8-24
WHO National policy on traditional medicine and regulation of herbal medicines
Geneva 20059-78
WHO Quality Control Methods for Medicinal Plants Materials Geneva 19981-
115
WHO Regulatory situation of herbal medicines a Worldwide Review
WHOTRM9811998 (b)
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 200440
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004a86
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004b3
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004c90
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004d 66
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004e67
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004f88
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
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Pharmacognosy Research 2 (5) (2010) 318-322
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Journal 4 (27) (2012) 20-24
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countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
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Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
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Q4
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Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
Q11
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Q13
Q14
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Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
References
[Development and Standardization of Modern Dosage Form for Indigenous Medicinal
Formulations] 204
WHO The Use of Traditional medicine in primary health care Delhi AITBS
publisher and distributor 2004g 98
WHO Traditional Medicine Programme WHOEDMTRM2000
WHO Traditional Medicine Strategy 2002-2005 6-86
WHO 2003 WHO guidelines on good agricultural and collection practices
(GACP) for medicinal plants World Health Organization Geneva
Williams M Curr Opin Pharmacol 2003 3 571-577
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
This article appeared in a journal published by Elsevier The attachedcopy is furnished to the author for internal non-commercial researchand education use including for instruction at the authors institution
and sharing with colleagues
Other uses including reproduction and distribution or selling orlicensing copies or posting to personal institutional or third party
websites are prohibited
In most cases authors are permitted to post their version of thearticle (eg in Word or Tex form) to their personal website orinstitutional repository Authors requiring further information
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Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
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8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
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17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
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Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
List of Publication
1 Ajazuddin Shailendra Saraf Applications of novel drug delivery system for
herbal formulations Fitoterapia 81 (7) (2010) 680ndash689
2 Ajazuddin Shailendra SarafEvaluation of physicochemical and
phytochemical properties of Safoof-E-Sana a Unani polyherbal formulation
Pharmacognosy Research 2 (5) (2010) 318-322
3 Ajazuddin Shailendra Saraf Development of Fingerprinting Methods of
Balacaturbhadrika Churna An Ayurvedic Formulation Pharmacognosy
Journal 4 (27) (2012) 20-24
4 Legal regulations of complementary and alternative medicines in different
countries Pharmacognosy Reviews (Article in Press)
5 Development of Fingerprinting Methods of Shingyadi Churna An Indian
integrative medicine Research Journal of Medicinal Plant (Communicated)
Manuscript ID (35993-RJMP-AJ)
6 Ajazuddin Shailendra Saraf Development and standardization of capsule
dosage form for some traditional Indian medicines Fitoterapia
(Communicated)
Papers presented in conferences
1 Ajazuddin Shailendra Saraf Development of fingerprinting methods for
Balacaturbhadrika churna An Ayurvedic formulation Poster NoC-359
62nd Indian Pharmaceutical Congress 2010 Manipal (KA) India
2 Shailendra Saraf Ajazuddin Swarnlata Saraf Development of fingerprinting
methods of Shringyadi churna an Indian alternative medicine Natural
Products Posters 5 September 2011 FIP Congress in Hyderabad (India)
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Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
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Contents lists available at ScienceDirect
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
This article appeared in a journal published by Elsevier The attachedcopy is furnished to the author for internal non-commercial researchand education use including for instruction at the authors institution
and sharing with colleagues
Other uses including reproduction and distribution or selling orlicensing copies or posting to personal institutional or third party
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httpwwwelseviercomcopyright
Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
Tel +91 7712262832 fax +91 7712263773E-mail address shailendrasarafrediffmailcom
0367-326X$ ndash see front matter copy 2010 Elsevier BV All rights reserveddoi101016jfitote201005001
Contents lists available at ScienceDirect
Fitoterapia
j ourna l homepage wwwe lsev ie rcom locate f i to te
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
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25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
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27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
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31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
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33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
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54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
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Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
Review
Applications of novel drug delivery system for herbal formulations
Ajazuddin S SarafUniversity Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur CG 492010 India
a r t i c l e i n f o a b s t r a c t
Article historyReceived 6 January 2010Accepted in revised form 28 April 2010Available online 12 May 2010
Over the past several years great advances have been made on development of novel drugdelivery systems (NDDS) for plant actives and extracts The variety of novel herbalformulations like polymeric nanoparticles nanocapsules liposomes phytosomesnanoemulsions microsphere transferosomes and ethosomes has been reported usingbioactive and plant extracts The novel formulations are reported to have remarkableadvantages over conventional formulations of plant actives and extracts which includeenhancement of solubility bioavailability protection from toxicity enhancement ofpharmacological activity enhancement of stability improved tissue macrophagesdistribution sustained delivery and protection from physical and chemical degradation Thepresent review highlights the current status of the development of novel herbal formulationsand summarizes their method of preparation type of active ingredients size entrapmentefficiency route of administration biological activity and applications of novel formulations
copy 2010 Elsevier BV All rights reserved
KeywordsHerbal drugsNovel drug delivery systems (NDDS)
Contents
1 Introduction 6802 Liposome 6813 Nanoparticles 6824 Phytosome 6825 Emulsions 6856 Other novel vesicular herbal formulations 6867 Microspheres 6868 Proprietary novel drug delivery system of plant actives and extracts 6869 Conclusion 687Acknowledgement 688References 688
1 Introduction
In the past few decades considerable attention has beenfocused on the development of novel drug delivery system
(NDDS) for herbal drugs The novel carriers should ideallyfulfill two prerequisites Firstly it should deliver the drug at arate directed by the needs of the body over the period oftreatment Secondly it should channel the active entity ofherbal drug to the site of action Conventional dosage formsincluding prolonged-release dosage forms are unable to meetnone of these In phyto-formulation research developing nano
Fitoterapia 81 (2010) 680ndash689
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Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
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[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q12
Q13
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Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
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Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
dosage forms (polymeric nanoparticles and nanocapsulesliposomes solid lipid nanoparticles phytosomes and nano-emulsion etc) have a number of advantages for herbal drugsincluding enhancement of solubility and bioavailability pro-tection from toxicity enhancement of pharmacological ac-tivity enhancement of stability improving tissuemacrophagesdistribution sustained delivery protection from physical andchemical degradation etc Thus the nano sized novel drugdelivery systems of herbal drugs have a potential future forenhancing the activity and overcoming problems associatedwith plant medicines Liposomes which are biodegradableand essentially non-toxic vehicles can encapsulate both hy-drophilic and hydrophobic materials [1] Liposome based drugdelivery systems offer the potential to enhance the therapeuticindex of anti-cancer agents either by increasing the drug con-centration in tumor cells andor by decreasing the exposurein normal tissues exploiting enhanced permeability and reten-tion effect phenomenon and by utilizing targeting strategies[2] The main advantages of using liposomes include i) thehigh biocompatibility ii) the easiness of preparation iii) thechemical versatility that allows the loading of hydrophilicamphiphilic and lipophilic compounds and iv) the simplemodulation of their pharmacokinetic properties by chang-ing the chemical composition of the bilayer components [3]Delivery of agents to the reticuloendothelial system (RES) iseasily achieved sincemost conventional liposomes are trappedby the RES [1] The application of novel approaches can alsoimprove the efficacy of herbal cosmetic formulations on thehuman body [4] Similarly the other vesicular systems likenanoemulsion ethosomes and transferosomes are highlyuseful assemblies and find various advantages in the deliveryof herbal medicines some of them are summarized in presentarticle
The phytosome process has also been applied to manypopular herbal extracts including Ginkgo biloba grape seedhawthorn milk thistle [5] green tea and ginseng Theflavonoid and terpenoid components of these herbal extractslend themselves quite well for the direct binding tophosphatidylcholine Phytosome is produced by bindingindividual components of herbal extracts to phosphatidylcholine resulting in a dosage form that is better absorbed andthus produces better results than the conventional herbalextracts [6] The results indicate that the absorption of silybinfrom silybin phytosome is approximately seven times greatercompared to the absorption of silybin from regular milkthistle extract [5] Drugs can be embedded or dissolved innanoparticles and can also be adsorbed or coupled on thesurface [7] Encapsulating drugs within NPs can improve thesolubility and pharmacokinetics of drugs and in some casesenable further clinical development of new chemical entitiesthat have stalled because of poor pharmacokinetic properties[8] The major carrier materials of nanoparticles are syntheticbiodegradable high molecular polymer and natural polymerThe former usually includes poly-α-cyanoacrylate alkylesters polyvinyl alcohol polylactic acid and polylacticco-glycolic acid etc The latter is usually divided into two classesproteins (albumin gelatin and vegetable protein) andpolysaccharides (cellulose starch and its derivatives alginatechitin and chitosan etc) [9]
In this article an attempt has been made to touch upondifferent aspects related to the development of novel herbal
formulations including method of preparation type of activeingredient entrapment efficiency and applications etc
2 Liposome
The liposomes are spherical particles that encapsulate afraction of the solvent in which they freely diffuse (float) intotheir interior They can have one several or multipleconcentric membranes Liposomes are constructed of polarlipids which are characterized by having a lipophilic andhydrophilic group on the same molecules [10] Uponinteraction with water polar lipids self-assemble and formself-organized colloidal particles Simple examples are deter-gents components form micelles while polar lipids withbulkier hydrophobic parts cannot associate into micelles withhigh curvature radii but form bilayers which can self-closeinto liposomes or lipid vesicles A cross-section of a liposome(Fig 1) depicts the hydrophilic heads of the amphiphileorienting towards the water compartment while the lipo-philic tails orient away from the water towards the center ofthe vesicle thus forming a bilayer Consequently watersoluble compounds are entrapped in the water compartmentand lipid soluble compounds aggregate in the lipid sectionUniquely liposomes can encapsulate both hydrophilic andlipophilic materials Liposomes usually formed from phos-pholipids have been used to change the pharmacokineticsprofile of not only drugs but herbs vitamins and enzymes Avariety of herbal liposomal formulations has been studiedwhich are summarized in Table 1 Because of their uniqueproperties liposomes are able to enhance the performance ofproducts by increasing ingredient solubility improvingingredient bioavailability enhanced intracellular uptake andaltered pharmacokinetics and biodistribution [9] and in vitroand in vivo stability Liposomes as a drug delivery system canimprove the therapeutic activity and safety of drugs mainlyby delivering them to their site of action and by maintainingtherapeutic drug levels for prolonged periods of time [11ndash13]
Milk thistle (Silybum marianum) is one of the few herbaldrugs whose excellent pharmacological profile readily lendsitself to proof of clinical efficacy [13] Meanwhile silymarin ispoorly absorbed (20ndash50) from the gastrointestinal tract [14]that causes the effects of silybin one of the main activeflavonoids commonly found in the dried fruits of silymarin tobe greater after parenteral than oral administration [15]
Fig 1 Cross-section of a liposome [4]
681Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
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54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
Incorporation of silymarin into liposomal dosage formadministered buccaly can improve its bioavailability In thisconnection to improve the bioavailability of silymarinthrough its incorporation in a stable liposomal buccal dosageform using commercially available soybean lecithin El-Samaligy et al [16] prepared silymarin encapsulated hybridliposomes which shows successful preparation with efficientencapsulation of silymarin Mixing silymarin loaded hybridliposomes with unloaded ones in a (11) proportion wasuseful in prevention of aggregates which threaten liposomalstability M50 proved stability regarding encapsulationefficiency turbidity measurement and particle size analysisafter 3 months of storage at 4 degC or at ambient temperatureRefrigeration is recommended to achieve better stability Theintroduced hybrid liposomal silymarin formula for buccaladministration have the advantages of exerting a mucoadhe-sive effect [17] besides its deformability due to the presenceof Tween 20 as edge activator allowing the medicatedliposomes to squeeze through buccal mucosal cells It wasalso shown to be safe upon contacting the rat buccal mucosa
3 Nanoparticles
In recent year the nanonization of herbal medicines hasattracted much attention [30] some of them are illustrated in
Table 2 Nanoparticles and nanoemulsions (Fig 2) arecolloidal systems with particles varying in size from 10 nmto 1000 nm [3132] Nanoparticle systems with mean particlesize well above the 100 nm standard have also been reportedin literature including nanonized curcuminoids [33] pacli-taxel [34] and praziquantel [35] which have a mean particlesize of 450 1477 and even higher than 200 nm respectivelyIn addition nanoparticles could also be defined as beingsubmicronic (b1 lm) colloidal systems [36] The nanosphereshave a matrix type structure in which the active ingredient isdispersed throughout (the particles) whereas the nanocap-sules have a polymeric membrane and an active ingredientcore Nanonization possesses many advantages such asincreasing compound solubility reducing medicinal dosesand improving the absorbency of herbal medicines comparedwith the respective crude drugs preparations [36]
4 Phytosome
Over the past century phytochemical and phytopharma-cological sciences established the compositions biologicalactivities and health promoting benefits of numerous plantproducts Most of the biologically active constituents of plantsare polar or water soluble molecules However water solublephytoconstituents (like flavonoids tannins terpenoids etc)
Table 1Liposomal herbal formulation
Formulations Activeingredients
Applications of liposomeformulations
Biological activity Method ofpreparation
Entrapmentefficiency
Route ofadministration
Reference
Quercetin liposomes Quercetin Reduced dose enhancepenetration in blood brainbarrier
AntioxidantAnticancer
Reverseevaporationtechnique
60 Intranasal [18]
Liposomesencapsulated silymarin
Silymarin Improve bioavailability Hepatoprotective Reverseevaporationtechnique
6922plusmn06
Buccal [16]
Liposoma artemisiaarborescens
Artemisiaarborescensessential oil
Targeting of essential oils tocells enhance penetrationinto cytoplasmatic barrier
Antiviral Film method andsonication
60ndash74 In vitro [19]
Ampelopsin liposome Ampelopsin Increase efficiency Anticancer Film-ultrasoundmethod
6230 In vitro [20]
Paclitaxel liposome Paclitaxel High entrapment efficiencyand PH sensitive
Anticancer Thin filmhydration method
94 In vitro [21]
Curcumin liposome Curcumin Long-circulating with highentrapment efficiency
Anticancer Ethanol injectionmethod
8827plusmn216
In vitro [22]
Garlicin liposome Garlicin Increase efficiency Lungs Reverse-phaseevaporationmethod
9077 ndash [23]
Flavonoids liposomes Quercetinand rutin
Binding of flavonoids with Hbis enhanced
Hemoglobin Solventevaporation
ndash In vitro [24]
Usnea acid liposome withβ-CD
Usnea acid Incrase solubility andlocalization with prolonged-release profile
Antimycobacterial Hydration of a thinlipid film methodwith sonication
995 In vitro [25]
Wogonin liposome Wogonin Sustained release effect Anticancer Film dispersionmethod
8120plusmn420
In vivo [26]
Colchicine Liposome Colchicine Enhance skin accumulationprolong drug release andimprove site specificity
Antigout Rotaryevaporationsonication method
663plusmn22 Topical [27]
Catechins liposomes Catechins Increased permeationthrough skin
Antioxidant andchemopreventive
Rotaryevaporationsonication method
930plusmn01 Transdermal [28]
Breviscapine liposomes Breviscapin Sustained delivery ofbreviscapine
Cardiovasculardiseases
Doubleemulsificationprocess
879plusmn31 Intramuscular [29]
682 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
Table2
Nan
ostructured
herbal
form
ulations
Form
ulations
Active
ingred
ients
App
lications
ofna
nostructured
form
ulations
Biolog
ical
activity
Metho
dof
prep
aration
En
trap
men
tefficien
cyRo
uteof
administration
Referenc
e
Triptolid
ena
nopa
rticle
Triptolid
eEn
hanc
ethepe
netrationof
drug
sthroug
hthe
stratum
corn
eum
byincrea
sedhy
dration
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Topical(
skin)
[30]
Nan
oparticles
ofCu
scuta
chinen
sis
Flav
onoids
andlig
nans
Improv
ewater
solubility
Hep
atop
rotectivean
dan
tiox
idan
teffects
Nan
osus
pens
ionmetho
d90
Oral
[37]
Triptolid
e-load
edsolid
lipid
nano
particle
Triptolid
eDecreasingthetoxicity
Anti-inflam
matory
Emulsification
-ultrasoun
dndash
Oral
[38]
Artem
isinin
nano
caps
ules
Artem
isinin
Sustaine
ddrug
release
Antican
cer
Self-
assemblyproc
edure
90ndash93
In
vitro
[39]
Radixsalvia
miltiorrhiza
nano
particles
Rsalvia
miltiorrhiza
Improv
ethebioa
vaila
bility
Corona
ryhe
artdiseasesa
ngina
pectoris
andmyo
cardialinfarction
Spray-drying
tech
niqu
eUpto96
68
Invitro
[40]
Taxe
l-load
edna
nopa
rticles
Taxe
lEn
hanc
ethebioa
vaila
bilityan
dsu
staine
ddrug
release
Antican
cer
Emulsion
solven
tev
aporation
metho
d99
44
ndash[41]
Berberine-load
edna
nopa
rticles
Berberine
Sustaine
ddrug
release
Antican
cer
Ionicge
lation
metho
d65
40plusmn
070
In
vitro
[42]
Silib
ini-load
edna
nopa
rticles
Silib
ini
Highen
trap
men
tefficien
cyan
dstab
ility
Hep
atop
rotective
Highpressu
reho
mog
enization
9564
ndash[43]
Tetran
drine-load
edna
nopa
rticles
Tetran
drine
Sustaine
ddrug
release
Lung
Self-
emulsification
andsolven
tev
aporating
84
Invitro
[44]
Glycy
rrhizicacid-loa
ded
nano
particles
Glycy
rrhizic
acid
Improv
ethebioa
vaila
bility
Anti-inflam
matory
antihy
perten
sive
Rotary-eva
porated
film
ultrason
icationmetho
d91
76
ndash[45]
Que
rcetin-loa
ded
nano
particles
Que
rcetin
Increa
sean
tiox
idan
tactivity
andreleaseof
the
drug
74times
high
erAntioxida
ntNan
oprecipitation
tech
niqu
eov
er99
In
vitro
[46]
Brev
iscapine
-loa
ded
nano
particles
Brev
iscapine
Prolon
gtheha
lf-lifean
dde
crea
seRE
Sup
take
Cardiova
scular
andcerebrov
ascu
lar
Spon
tane
ousem
ulsification
solven
tdiffus
iontech
niqu
e93
1
IntraVen
ous
[47]
Zedo
aryturm
eric
oil
nano
caps
ule
Zedo
ary
turm
eric
oil
Increa
sethedrug
load
ingan
dstab
ility
ofZT
OHep
atop
rotectionAntican
ceran
dan
ti-bacterial
Highpressu
reHom
ogen
izationmetho
d162
plusmn015
Lo
adingCa
pacity
ndash[48]
Naringe
nin-
load
edna
nopa
rticles
Naringe
nin
Improv
edthereleaseof
NARan
dim
prov
editssolubility
Hep
atop
rotective
Nan
oprecipitation
metho
dndash
Oral
[49]
Curcum
inoids
solid
lipid
nano
particles
Curcum
inoids
Prolon
ged-releaseof
thecu
rcum
inoids
Antican
ceran
dan
tiox
idan
tMicro-emulsion
tech
niqu
e70
In
vitro
[50]
CPT-en
caps
ulated
nano
particles
Camptothe
cin
Prolon
gedbloo
dcirculationan
dhigh
accu
mulationin
tumors
Antican
cer
Dialysismetho
dN80
In
vitro
[51]
Ginkg
obiloba
nano
particles
Ginkg
obiloba
extract
Improv
ingthecerebral
bloo
dflow
and
metab
olism
Brainfunc
tion
activa
tion
Highpressu
reho
mog
enization
metho
dndash
Oral
[52]
683Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
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Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
are poorly absorbed either due to their large molecular sizewhich cannot absorb by passive diffusion or due to their poorlipid solubility severely limiting their ability to pass acrossthe lipid-rich biological membranes resulting poor bioavail-ability [53] It has often been observed that the isolation andpurification of the constituents of an extract may lead to apartial or total loss of specific bio-activity for the purifiedconstituent mdash the natural constituent synergy becomes lostVery often the chemical complexity of the crude or partiallypurified extract seems to be essential for the bioavailability ofthe active constituents Extracts when taken orally someconstituents may be destroyed in the gastric environment Asstandardized extracts are established poor bioavailabilityoften limits their clinical utility due to above said reasons It
has been observed that complexation with certain otherclinically useful nutrients substantially improves the bio-availability of such extracts and their individual constituentsThe nutrients so helpful for enhancing the absorption are thephospholipids Phytosome is a patented technology devel-oped by a leading manufacturer of drugs and nutraceuticalsto incorporate standardized plant extracts or water solublephytoconstituents into phospholipids to produce lipid com-patible molecular complexes called as phytosomes and sovastly improve their absorption and bioavailability [54](Table 3) In liposomes no chemical bond is formed thephosphatidylcholine molecules surround the water solublesubstance There may be hundreds or even thousands ofphosphatidylcholine molecules surrounding the water solu-ble compound In contrast with the phytosome process thephosphatidylcholine and the plant components actually forma 11 or a 21 molecular complex depending on the substance(s) complexed involving chemical bonds (Fig 3) Phospho-lipids are complex molecules that are used in all known lifeforms to make cell membranes In humans and other higheranimals the phospholipids are also employed as naturaldigestive aids and as carriers for both fat-miscible and watermiscible nutrients They are miscible both in water and inlipid environments and are well absorbed orally Phytosomesare more bioavailable as compared to conventional herbalextracts owing to their enhanced capacity to cross the lipoidalbiomembrane and finally reaching the systemic circulation
Fig 2Cross-section of (a) nanoemulsion and (b) biopolymeric nanoparticle [4]
Table 3Phytosomal herbal formulations
Formulations Activeingredients
Applications of phytosomal formulations Biological activity Method ofpreparation
Dose Route ofadministration
Reference
Ginkgo bilobaphytosomes
Flavonoids Flavonoids of GBP stabilize the ROS Cardio-protectiveantioxidantactivity
Phospholipidscomplexation
100 mgand200 mgkg
Subcutaneous [55]
Ginkgoselectphytosome
Flavonoids Inhibits lipid peroxidation (LPO)stabilize the ROS
Hepatoprotectiveantioxidant
Phospholipidscomplexation
25 and50 mgkg
Oral [56]
Silybinphytosome
Flavonoids Absorption of silybin phytosomefrom silybin is approximatelyseven times greater
Hepatoprotectiveantioxidant forliver and skin
Silybin-phospholipidcomplexation
120 mg Oral [57]
Ginsengphytosome
Ginsenosides Increase absorption Nutraceuticalimmunomodulator
Phospholipidscomplexation
150 mg Oral [58]
Green teaphytosome
Epigallocatechin Increase absorption Nutraceuticalsystemicantioxidant anti-cancer
Phospholipidscomplexation
50ndash100 mg
Oral [58]
Grape seedphytosome
Procyanidins The blood TRAP nTotal Radical-trappingAntioxidant Parameter) were significantlyelevated over the control
Systemicantioxidantcardio-protective
Phospholipidscomplexation
50ndash100 mg
Oral [58]
HawthornPhytosome
Flavonoids Increase therapeutic efficacyand absorption
Cardio-protectiveandantihypertensive
PhospholipidsComplexation
100 mg Oral [58]
Quercetinphytosome
Quercetin Exerted better therapeutic efficacy Antioxidantanticancer
Quercetinndashphospholipidcomplexation
ndash Oral [59]
Curcuminphytosomes
Curcumin Increase antioxidant activity andIncrease bioavailability
Antioxidantanticancer
Curcuminndashphospholipidcomplexation
360 mgkg
Oral [60][49]
Naringeninphytosomes
Naringenin Prolonged duration of action Antioxidantactivity
Naringeninndashphospholipidcomplex
100 mgkg
Oral [61]
684 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
Phytosome has been an emerging trend in delivery of herbaldrugs and nutraceuticals
5 Emulsions
Emulsion refers to a non-homogeneous dispersion systemthat is composed of two kinds of liquids unable to dissolve eachother and one of which disperse in the other one in a form ofdroplets [62] Generally emulsion is composed of oil phase
water phase surfactant and sub-surfactant Its appearance istranslucent to transparent liquid Emulsion can be classifiedinto ordinary emulsion (01ndash100 μm) micro-emulsion (10ndash100 nm) sub-micro-emulsion (100ndash600 nm) etc (Table 4)Among them themicro-emulsion is also called nanoemulsionsand the sub-micro-emulsion is also called lipid emulsion As adrug delivery system emulsion distributes in vivo in thetargetedmanner due to its affinity to the lymph In addition thedrug can be sustained release in a long time because the drug ispackaged in the inner phase and kept off direct touch with thebody and tissue fluid [63] After the oily drugs or lipophilicdrugs beingmade intoOWorOWOemulsion the oil dropletsare phagocytosised by the macrophage and get a highconcentration in the liver spleen and kidney in which theamount of the dissolved drug is very largeWhilewater solubledrug is produced intoWO orWOW emulsion it can be easilyconcentrated in the lymphatic system by intramuscular orsubcutaneous injection The size of the emulsion particle has animpact on its target distribution
Apart from its targeted sustained release producing theherbal drug into emulsion will also strengthen the stability ofthe hydrolyzedmaterials improve the penetrability of drugs tothe skin andmucous and reduce the drugs stimulus to tissuesSo far somekinds of herbal drugs suchas camptothecinBruceajavanica oil coixenolide oil and zedoary oil have been madeinto emulsion For example Zhou et al [64] studied theinfluence of the elemenum emulsion on the human lungadenocarcinoma cell line A549 and protein expression Resultsshowed that the elemenum emulsion has a significantinhibition on the growth and proliferation of the A549 invitro and it showed a time and dose-dependent relationshipElemenum emulsion is a type of new anti-cancer drug withgreat application prospects Furthermore it has no marrowinhibition and no harm to the heart and liver
Fig 3 Difference between liposome and phytosome [58]
Table 4Emulsion herbal formulations
Formulations Activeingredients
Applications ofemulsionformulations
Biological activity Method of preparation Dropletsize
Drugloading
Route ofadministration
Reference
Self-nanoemulsifyingZedoary essential oil
Zedoaryturmericoil
Improved aqueousdispersibilitystability and oralbioavailability
Hepatoprotectionanticancer andanti-bacterial
Drawing ternary phaseDiagram
683plusmn16 nm
30 Oral [65]
Triptolide micro-emulsion
Triptolide Enhance thepenetration ofdrugs through thestratum corneumby increasedhydration
Anti-inflammatory
High pressureHomogenization method
b100 nm ndash Topical [30]
Docetaxel submicronemulsion
Docetaxel Improve residencetime
Anticancer High pressureHomogenization method
16600 nm 90 Intravenous [66]
Berberinenanoemulsion
Berberine Improve residencetime andabsorption
Anticancer Drawing ternary phasediagram
5680 nm 050 Oral [67]
Silybin nanoemulsion Silybin Sustained releaseformulation
Hepatoprotective Emulsification method 2120 nm ndash Intramuscular [68]
Quercetin micro-emulsion
Quercetin Enhancepenetration intostratum corneumand epidermis
Antioxidant High speedHomogenization method
10ndash100 nm
03solution
Topical [69]
685Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
200614301ndash10[3] Terreno E Castelli DD Cabellab C Dastru W Saninoa A Stancanellob J
et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
6 Other novel vesicular herbal formulations
Transferosomes are applied in a non-occluded method tothe skin which permeate through the stratum corneum lipidlamellar regions as a result of the hydration or osmotic forcein the skin It can be applicable as drug carriers for a range ofsmall molecules peptides proteins and herbal ingredientsTransferosomes can penetrate stratum corneum and supplythe nutrients locally to maintain its functions resultingmaintenance of skin [70] in this connection the transfero-somes of Capsaicin has been prepared by Xiao-Ying et al [71]which shows the better topical absorption in comparison topure capsaicin Ethosome as a novel liposome is especiallysuitable as a topical or transdermal administration carrier[7273] Ethosome has a high deformability and entrapmentefficiency and can penetrate through the skin completely andimprove drug delivery through the skin Compared to otherliposomes the physical and chemical properties of ethosomesmake the delivery of the drug through the stratum corneuminto a deeper skin layer efficiently or even into the bloodcirculation [74] This property is very important as the topicaldrug carrier and transdermal delivery system Moreover theethosomes carrier also can provide an efficient intracellulardelivery for both hydrophilic and lipophilic drugs [75]percutaneous absorption of matrine an anti-inflammatoryherbal drug is increased [76] it also permits the antibacterialpeptide to penetrate into the fibrocyte easily [77] The roles ofthese types of novel vasicular system over herbal drugdelivery are summarized in (Table 5)
7 Microspheres
Administration of medication via micro particulate sys-tems is advantageous because microspheres can be ingestedor injected and they can be tailored for desired releaseprofiles and used site-specific delivery of drugs and in somecases can even provide organ-targeted release [80] So far aseries of plant active ingredients such as rutin camptothecinzedoary oil tetrandrine quercetine and Cynara scolymusextract has been made into microspheres (Table 6) Inaddition reports on immune microsphere and magneticmicrosphere are also common in recent years Immunemicrosphere possesses the immune competence as a resultof the antibody and antigen was coated or adsorbed on thepolymer microspheres
8 Proprietary novel drug delivery system of plant activesand extracts
Cosmetochem International AG is a Swiss-based companyspecialized in the production of high quality customizedbotanical extracts and actives launch botanical standardizedliposomal powders named Liposome Herbasecreg [86] a novelrange of standardized botanical extracts in a liposomal-basedpowder form As the liposome carriers are very effectivepenetration enhancers which serve as carriers to the skinincreasing the bioavailability of the plant extracts In presentformulation the freeze-dried dispersion of Liposome Herba-secreg is reformed when dispersed in water re-encapsulating
Table 5Other novel vesicular herbal formulations
Formulations Active ingredients Applications Biologicalactivity
Droplet size Route ofadministration
Reference
Capsaicin transferosomes Capsaicin Increase skin penetration Analgesic 1506 nm Topical [71]Colchicine transferosomes Colchicine Increase skin penetration Antigout ndash In vitro [77][79]Vincristine transferosomes Vincristine Increase entrapment efficiency and skin
permeation yAnticancer 120 nm In vitro [77]
Matrine ethosome Matrine Improve the percutaneous permeation Anti-inflammatory
110plusmn8 nm Topical [76]
Ammonium glycyrrhizinateethosomes
Ammoniumglycyrrhizinate
Increase of the in vitro percutaneouspermeation
Anti-inflammatory
350 nm to100 nm
Topical [78]
Table 6Microspheres encapsulated herbal formulations
Formulations Activeingredients
Applications offormulations
Biological activity Method ofpreparation
Size inmicrom
Route ofadministration
Reference
Rutinndashalginatendashchitosanmicrocapsules
Rutin Targeting into cardiocascularand cerebrovascular region
Cardiovascular andCerebrovasculardiseases
Complex-coacervation method
16500ndash19500
In vitro [81]
Zedoary oilmicrosphere
Zedoary oil Sustained release and Higherbioavailability
Hepatoprotective Quasi-emulsionndashsolvent diffusionmethod
100ndash600
Oral [82]
CPT loadedmicrospheres
Camptothecin Prolonged-release ofcamptothecin
Anticancer Oil-in-waterevaporation method
10 Intraperitoneallyand intravenously
[83]
Quercetinmicrospheres
Quercetin Significantly decreases thedose size
Anticancer Solvent evaporation 6 In vitro [84]
Cynara scolymusmicrospheres
Cynarascolymusextract
Controlled release ofneutraceuticals
Nutritionalsupplement
Spray-dryingtechnique
6ndash7 Oral [85]
686 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
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2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
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4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
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8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
the concentrated plant extract Phospholipids used for thepreparation of formulation are the safest mildest substanceswhich allow the penetration of the plant actives into thedeeper layers of the epidermis and avoid the use of solventsThere are five extracts in the current Liposome Herbasecregrange (Table 7) which are standardized for specific phyto-chemicals White and green tea are standardized for caffeineand total polyphenols white hibiscus for fruit acids guaranafor caffeine and aloe vera is aloin-free [86] LiposomeHerbasecreg can be used in a wide range of personal careapplications Smilarly based on Phytosomereg technology aline of products has been developed and commercialized byIndena [87] (Table 7) The Phytosomereg formulation increasesthe absorption of active ingredients when topically appliedon the skin [88ndash97] and improves systemic bioavailabilitywhen administered orally [98ndash102] A Phytosomereg is gen-erally more bioavailable than a simple herbal extract dueto its enhanced capacity to cross the lipid-rich biomembranesand reach circulation [103ndash105] To overcome the poor bio-availability of silybin Indena has complexed it with soyphospholipids exploiting the Phytosomereg technology Asdemonstrated by comparative pharmacokinetic studiesSilipidereg represents the most absorbable oral form of silybinknown The pharmacokinetics of Silipidereg in healthy humansubjects showed that complexationwith phosphatidylcholineimproved the oral bioavailability of silybin 46 fold comparedwith silymarin presumably because of a facilitated passageacross the gastrointestinal mucosa [97] The good bioavail-ability of Siliphosreg was confirmed in a human pharmacoki-netic study in prostate cancer patients The study employedhigh dosages and was aimed at getting information ontoxicity and phase II dosage of the product Siliphosreg at adaily oral dose of 13 g in 3 divided doses waswell tolerated inall patients and this dosage was recommended for the phase
II study [106]The results including the optimal tolerabilityobtained in these ldquoextremerdquo clinical situations provide strongsupport for the use of Siliphosreg also in less severe pathologiesassociated with liver damage Ginkgoselectreg Phytosomeregwas administered at a dosage of 360 mgday (120 mg threetimes per day) to 22 subjects affected by the Raynaudsdisease in a double-blind placebo-controlled trial Patientswere required to record the frequency and duration of anyvasospastic attack also completing a scoring scale of theoverall perception of the severity of the episodes Patientswere reviewed after two four and ten weeks of treatmentThis pilot study showed the efficacy of GinkgoselectregPhytosomereg in promoting a clear and highly statisticallysignificant reduction in the frequency (56) and severity ofRaynauds attacks per day [107] Merivareg is a patentedcomplex of curcumin a dietary phenolic with soy phospha-tidylcholine [108] A lot of work that has been published inthe journal Cancer Chemotherapy and Pharmacology [109]demonstratedMerivaregs superior bioavailability compared toa standardized curcumin extract in rats while very promisinginitial preclinical results in terms of improved hydrolyticalstability and human pharmacokinetics have been shownmore recently[108] Including the advantages of these abovementioned commercialized NDDS preparation of plantactivesextracts a variety of other preparations is alsoavailable (Table 7) which show the remarkable advantagesover pure plant activesextracts
9 Conclusion
An extensive research is going on in the area of novel drugdelivery and targeting for plant actives and extracts How-ever research in this area is still at the exploratory stageMany problems in the research production and application
Table 7Marketed novel drug delivery formulations of plant active and extracts
SN Brand name Plant activeextracts Type ofNDDS
Companyname
Reference
1 White tea liposome Herbasecreg Camellia sinensis extract Liposome Cosmetochem [86]2 Green tea liposome Herbasecreg Camellia sinensis Extract Liposome Cosmetochem [86]3 White hibiscus liposome Herbasecreg White hibiscus extract Liposome Cosmetochem [86]4 Aloe vera liposome Herbasecreg Aloe vera Extract Liposome Cosmetochem [86]5 Guarana liposome Herbasecreg Guarana extract Liposome Cosmetochem [86]6 18szlig-glycyrrhetinic acid Phytosomereg 18szlig-glycyrrhetinic acid from licorice rhizome Phytosome Indena [87]7 Centella Phytosomereg Triterpenes from Centella asiatica leaf Phytosome Indena [87]8 Crataegus Phytosomereg Vitexin-2Prime-O-rhamnoside from Hawthorn flower Phytosome Indena [87]9 Escin szlig-sitosterol Phytosomereg Escin szlig-sitosterol from horse chestnut fruit Phytosome Indena [87]10 Ginkgoselectreg Phytosomereg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
11 Ginselectreg Phytosomereg Ginsenosides from Panax ginseng rhizome Phytosome Indena [87]12 Ginkgo biloba terpenes Phytosomereg Ginkgolides and bilobalide from Ginkgo biloba leaf Phytosome Indena [87]13 Ginkgo biloba dimeric flavonoids Phytosomereg Dimeric flavonoids from Ginkgo biloba leaf Phytosome Indena [87]14 Greenselectreg Phytosomereg Polyphenols from green tea leaf Phytosome Indena [87]15 Leucoselectreg Phytosomereg Polyphenols from grape seed Phytosome Indena [87]16 Merivareg Curcuminoids from turmeric rhizome Phytosome Indena [87]17 PA2 Phytosomereg Proanthocyanidin A2 from horse chestnut bark Phytosome Indena [87]18 Sericoside Phytosomereg Sericoside from Terminalia sericea bark root Phytosome Indena [87]19 Siliphosreg Silybin from milk thistle seed Phytosome Indena [87]20 Silymarin Phytosomereg Silymarin from milk thistle seed Phytosome Indena [87]21 Virtivareg Ginkgoflavonglucosides ginkgolides bilobalide from
Ginkgo biloba leafPhytosome Indena [87]
22 Visnadexreg Visnadin from Ammi visnaga umbel Phytosome Indena [87]
687Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
References
[1] Medina OP Zhu Y Kairemo K Curr Pharm Des 2004102981ndash9[2] Sharma G Anabousi S Ehrhardt C Kumar MNVR J Drug Target
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et al Chem Biodivers 200851901ndash2[4] Chanchal D Swarnlata S J Cosmet Dermatol 2008789ndash95[5] Barzaghi N Eur J Drug Metab Pharmacokinet 199015(4)333ndash8[6] wwwdoctormurraycomarticlesphytosomes html[7] Yuan DF Yi YM Her Med 200322113ndash4[8] Alexis F Basto P Levy-Nissenbaum E Radovic-Moreno AF Zhang LF
Pridgen E et al Chem Med Chem 200831839ndash43[9] Xiao YL Li B Chine Trad Herb Drugs 200233385ndash8
[10] Lasic DD lsquoLiposomes From Physics to Applicationsrsquo Elsevier Amster-damLondon New York Tokyo 1993
[11] Abou El Wafa AA Mursi NM El-Shaboury KM A pharmaceuticl studyon certain ocular drug delivery systems MS Thesis Cairo UnivercityCairo 2003
[12] Barragan-Montero V Winum J Moles J Juan E Clavel C Montero J EurJ Med Chem 2005401022ndash9
[13] Weiss R Fintelmann V Herbal medicine 2nd ed Stuttgart New YorkThieme 2000
[14] Blumenthal M Goldberg A Brinkmann J Herbal medicine IntegrativeMedicine Communications Newton 2000
[15] Carini R Comogoliom A Albano A Poli G Biochem Pharmacol1992432111ndash5
[16] El-Samaligy MS Afifi NN Mahmoud EA Int J Pharm 2006319121ndash9[17] Takeuchi H Matsui Y Yamamoto H Kawashima Y 2003 J Control
Release 200386235ndash42[18] Aroonsri P Jintanaporn W Saengrawee S Wathita P Supaporn M
Nanomed Nanotechnol Biol Med 2008470ndash8
[19] Chiara S Alessandro DL Francesco L Donatella V Maria M Giuseppe Let al Eur J Pharm Biopharm 200559161ndash8
[20] He ZF Liu DY Zeng S Ye JT J Chine Mat Med 20083327ndash30[21] Rane S Prabhakar B Int J Pharm Technol Res 20091914ndash7[22] Hong W Chen DW Zhao XL Qiao MX Hu HY China J Chine Mat Med
200833889ndash92[23] Sun P Den SH Yu WP J Shand Univ TCM 20073137ndash9[24] Juqun X Rong G Int J Biol Macromol 200740305ndash11[25] Lira MCB FerrazMS da Silva DGVC Cortes ME Teixeira KI Caetano NP
Santos-Magalhatildees NS J Incl Phenom Macrocycl Chem 200964215ndash24
[26] Ke X Xu Y Yan F Ping QN J China Pharm Univ 200738502ndash6[27] Godin B Touitou E J Control Release 200494(2ndash3)365ndash79[28] Fang J Hwang T Huang Fang C Int J Pharm 2006310(1ndash2)131ndash8[29] Zhong H Deng Y Wang X Yang B Int J Pharm 2005301(1ndash2)15ndash24[30] Zhinan M Huabing C Ting W Yajiang Y Xiangliang Y Eur J Pharm
Biopharm 200356189ndash96[31] Ratnam DV Ankola DD Bhardwaj V Sahana DK Kumar MN J Control
Release 2006113189ndash207[32] Alleacutemann E Gurny R Doelker E Eur J Pharm Biopharm 199339
173ndash91[33] Tiyaboonchai W Tungpradit W Plianbangchang P Int J Pharm
2007337299ndash306[34] Arica YB Benoit JP Lamprecht A Drug Dev Ind Pharm 200632
1089ndash94[35] Mainardes RM Evangelista RC Int J Pharm 2005290137ndash44[36] Brigger I Dubernet C Couvreur P Adv Drug Deliv Rev 200254
631ndash51[37] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Food Chem Toxicol 2008461771ndash7[38] Zhinan M Xiaokuan L Qunrong W Sheng H Xiangliang Y Pharmacol
Res 200551345ndash51[39] Youfang C Xianfu L Hyunjin P Richard G Nanomed Nanotechnol Biol
Med 20095316ndash22[40] Su YL Fu ZY Zhang JY Wang WM Wang H Wang YC et al Powder
Technol 2008184114ndash21[41] Fu RQ He FC Meng DS Chen L ACTA Academiae medicinae militaris
tertiae 28 2006 p 1573ndash4[42] Lin AH Li HY Liu YM Qiu XH China Pharm 200718755ndash7[43] Li YC Dong L Jia K Chang XM Xue H J Xian Jiaotong University (Med
Sci) 200728517ndash20[44] Xiaoyan A Jun Y Min W Haiyue Z Li C Kangdec Y et al Int J Pharm
2008350(1ndash2)257ndash64[45] Hou J Zhou SW ACTA Academiae medicinae militaris tertiae 200830
1043ndash5[46] Tzu-Hui W Feng-Lin Y Liang-Tzung L Tong-Rong T Chun-Ching L
Thau-Ming C Int J Pharm 2008346(1ndash2)160ndash8[47] Liu M Li H Luo G Liu Q Wang Y Arch Pharm Res 200831(4)
547ndash54[48] Lertsutthiwong P Noomun K Jongaroonngamsang N Rojsitthisak P
Carbohydr Polym 200874209ndash14[49] Feng-Lin Y Tzu-Hui W Liang-Tzung L Thau-Ming C Chun-Ching L
Pharm Res 200926(4)893ndash902[50] Mukerjee A Vishwanatha JK Anticancer Res 200929(10)3867ndash75[51] Min KH Park K Kim YS Bae SM Lee S Jo HG et al J Control Release
2008127208ndash18[52] Shimada S Composition comprising nanoparticle Ginkgo biloba extract
with the effect of brain function activation IPC8 Class-AA61K914FIUSPC Class-424489 2008
[53] Manach C Scalbert A Morand C Am J Clin Nutr 200479727ndash47[54] Bombardelli E Curri SB Loggia DR Del NP Tubaro A Gariboldi P
Fitoterapia 1989601ndash9[55] Vandana SP Suresh RN Exp Toxicol Pathol 200860397ndash404[56] Suresh RN Vandana SP Fitoterapia 200879439ndash45[57] Yanyu X Yunmei S Zhipeng C Quineng P Int J Pharm 2006 3 307(1)
77ndash82[58] Bhattacharya S Pharma Times 200941(3)9ndash12[59] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PK
Iran J Pharmacol Ther 2005484ndash90[60] Maiti K Mukherjee K Gantait A Saha BP Mukherjee PK Int J Pharm
2007330(1ndash2)155ndash63[61] Maiti K Mukherjee K Gantait A Bishnu PS Mukherjee PK J Pharm
Pharmacol 2006581227ndash33[62] Zhang Y Chin Tradition Herbal Drugs 200637641ndash7[63] Lu MF Cheng YQ Li LJ Wu JJ Mater Rev 200519108ndash10[64] Zhou X Li LY Guo ZJ Chin Clin Oncol 20049229ndash34[65] Zhaoa Y Wanga C Albert HL Chowb KR Gongc T Zhangc Z et al Int J
Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
200712736ndash9
688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
wwwphcogrevcom
DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
need to be solved In addition more attention should be paidto the research on the carrier materials in order to developmore suitable carriers which can reduce the toxicity of drugsenhance their activity and improve the overall quality of theagents Herbal drugs have enormous therapeutic potentialwhich should be explored through some value added drugdelivery systems Lipid solubility and molecular size are themajor limiting factors for drug molecules to pass the bio-logical membrane to be absorbed systematically followingoral or topical administration Several plant extracts andphytomolecules despite having excellent bio-activity in vitrodemonstrate less or no in vivo actions due to their poor lipidsolubility or improper molecular size or both resulting poorabsorption and poor bioavailability Standardized plantextracts or mainly polar phytoconstituents like flavonoidsterpenoids tannins xanthones when administered throughnovel drug delivery system show much better absorptionprofile which enables them to cross the biological membraneresulting enhanced bioavailability Hence more amount ofactive constituent becomes present at the site of action (liverbrain heart kidney etc) at similar or less dose as comparedto the conventional plant extract or phytomolecule Hencethe therapeutic action becomes enhanced more detectableand prolonged Several excellent phytoconstituents havebeen successfully delivered using NDDS Hence there is agreat potential in the development of novel drug deliverysystems for the plant actives and extracts
Acknowledgement
The authors acknowledge the University Grant Commis-sion [F no 34-1312008 (SR)] New Delhi INDIA for financialsupport
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Pharm 2010383(1ndash2)170ndash7[66] Li L Wang DK Li LS Jia J Chang D Ai L J Shenyang Pharm Univ
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688 Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
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Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
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728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
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oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
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24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
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32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
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8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
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Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
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56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
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national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Authors personal copy
[67] Sun HW Ouyang WQ J Shanghai Jiaotong Univ (Agric Sci) 2007160ndash5
[68] Song YM Ping QN Wu ZH J China Pharm Univ 20055427ndash31[69] Fabiana TMCV Thaıacutes RMS Jose ODC Nilce OW Dimitrius LP Mamie
MI et al Eur J Pharm Biopharm 200869948ndash57[70] Benson HA Expert Opin Drug Deliv 20066727ndash37[71] Xiao-Ying L Luo JB Yan ZH Rong HS HuangWM Zhongguo Zhong Yao
Za Zhi 200631(12)981ndash4[72] Jain S Tiwary AK Sapra B AAPS PharmSciTech 20078E111[73] Fang YP Tsai YH Wu PC Int J Pharm 2008356(1ndash2)144ndash52[74] Dayan N Touitou E Biomaterials 2000211879ndash85[75] Touitou E Godin B Dayan N Biomaterials 2001223053ndash9[76] Zhaowu Z Xiaoli W Yangdel Z Nianfeng L J Liposome Res 200919(2)
155ndash62[77] Zheng Y Hou SX Chen T Lu Y China J Chin Mater Med 200631(9)
728ndash31[78] Paolino D Lucania G Mardente D Alhaique F Fresta M J Control
Release 200510699ndash110[79] Singh HP Utreja P Tiwary AK Jain S AAPS J 2009254ndash64[80] Sanli O Karaca I Isiklan N J Appl Polym Sci 20091112731ndash40[81] Xiao L Zhang YH Xu JC Jin XH Chine Trad Herb Drugs 20082209ndash12[82] You J Cui F Han X Wang Y Yang L Yu Y et al Colloids Surf B 200648
(1)35ndash41[83] Machida Y Onishi H Kurita A Hata H Morikawa A Machida Y J
Control Release 200066(2ndash3)159ndash75[84] Chao P Deshmukh M Kutscher HL Gao D Rajan SS Hu P et al
Anticancer Drugs 201021(1)65ndash76[85] Gavini E Alamanni MC Cossu M Giunchedi P J Microencapsul
200522(5)487ndash99[86] httpwwwcosmetochemcom[87] httpwwwphytosomesinfopublicbioavailabilityasp[88] Bombardelli E Curri SB Gariboldi PG Fitoterapia 19896055ndash70[89] Bombardelli E Boll Chim Farma 1991130431ndash8[90] Bombardelli E (Indena SPA) Pharmaceutical and cosmetic composi-
tions containing complexes of flavanolignans with phospholipidsPatent EP0300282B1 1992
[91] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinsand their aglycons with phospholipids and pharmaceutical andcosmetic compositions containing them Patent US5166139 1992
[92] Bombardelli E Patri G (Indena SpA) Complex compounds ofbioflavonoids with phospholipids their preparation and use andpharmaceutical and cosmetic compositions containing them PatentEP0275005B1 1993
[93] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of saponinswith phospholipids and pharmaceutical and cosmetic compositionscontaining them Patent EP0283713B1 1993
[94] Bombardelli E Sabadie M (Indena SpAndashSanofi SA) Phospholipidiccomplexes of Vitis vinifera extracts process for their preparation andpharmaceutical and cosmetic compositions containing them PatentEP0300282B1 1993
[95] Di Pierro F (Indena SpA) Pharmaceutical and cosmetic compositionsagainst skin aging Patent EP0283713B1 1993
[96] Bombardelli E Cristoni A Morazzoni P Fitoterapia 199465387ndash401[97] Bombardelli E Patri G Pozzi R (Indena SpA) Complexes of neolignan
derivatives with phospholipids the use thereof and pharmaceuticaland cosmetic formulations containing them Patent EP0464297B11995
[98] Barzaghi N Crema F Gatti G Pifferi G Perucca E Eur J Drug MetabPharmacokinet 199015333ndash8
[99] Morazzoni P Magistretti MJ Giachetti C Zanolo G Eur J Drug MetabPharmacokinet 19921739ndash44
[100] Morazzoni P Montalbetti A Malandrino S Pifferi G Eur J Drug MetabPharmacokinet 199318289ndash97
[101] Maiti K Mukherjee K Gantait A Ahamed HN Saha BP Mukherjee PKIran J Pharmacol Ther 2005484ndash90
[102] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WPGescher AJ Cancer Chemother Pharmacol 200760171ndash7
[103] Mauri PL Simonetti P Gardana C Minoggio M Morazzoni PBombardelli E Rapid Commun Mass Spectrom 200115929ndash34
[104] Kidd PM Head K Altern Med Rev 200510193ndash203[105] Rossi R Basilico F Rossoni G Riva A Morazzoni P Mauri PL J Pharm
Biomed Anal 200950224ndash7[106] Flaig TW Gustafson DL Su L Zirrolli JA Crighton F Harrison GS Invest
New Drugs 200725139ndash46[107] Muir AH Robb R McLaren M Daly F Belch J Vasc Med 20027265ndash7[108] Kidd PM Alt Med Rev 200914226ndash46[109] Marczylo TH Verschoyle RD Cooke DN Morazzoni P Steward WP
Gescher AJ Cancer Chemother Pharmacol 200760(2)171ndash7
689Ajazuddin S Saraf Fitoterapia 81 (2010) 680ndash689
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
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17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
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36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
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41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
234 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Legal regulations of complementary and alternative medicines in different countriesAjazuddin Shailendra Saraf
University Institute of Pharmacy Pt Ravi Shankar Shukla University Raipur Chhattisgarh India
Submitted 25-03-2011 Revised -- Published --
Q1
R E V I E W A R T I C L EP H C O G R E V
Address for correspondenceMr Ajazuddin University Institute of Pharmacy Pt RSU Raipur Chhattisgarh IndiaE-mail write2ajazgmailcom
Traditional medicines that formed the basis of health care throughout the world since the earliest days of mankind are still widely used and have considerable importance in international trade Recognition of their clinical pharmaceutical and economic value is still growing although this varies widely between countries and therefore regulation of exploitation and exportation is essential together with international cooperation and coordination for their conservation so as to ensure their availability for the future World Health Organization and European Union issued the guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products Legislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them The present review highlights the status of different countries adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy
Key words Effi cacy legislation quality safety traditional medicines
A B S T R A C T
INTRODUCTION
During the past decade complementary and alternative medicines have become a topic of global importance Current estimates suggest that in many developing countries a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary healthcare needs Although modern medicine may be available in these countries herbal medicines (phytomedicines) have often maintained popularity for historical and cultural reasons Concurrently many people in developed countries have begun to turn to alternative or complementary therapies including medicinal herbs World Health Organization (WHO) estimated that the world market for herbal medicines and herbal products is worth US$ 62 billion and would hit US$ 5 trillion by 2050 The market is growing at 7 per annum (The Times of India 7-4-2000)
A common feature of most systems of traditional medicine (TM)complementary and alternative medicine (CAM) is that they take a holistic approach to promote health prevent disease and help the individual treat disturbances by regulating hisher physical emotional and mental aspects and living environment According to its characteristics and concepts TMCAM can be used not only for curing disease and relieving symptoms but also for the regulation improvement and promotion of the function of the human body Few plant species that provide medicinal herbs have been scientifi cally evaluated for their possible medical application Safety and effi cacy data are available for even fewer plants their extracts and active ingredients and the preparations containing them Furthermore in most countries the herbal medicinesrsquo market is poorly regulated and herbal products are often neither registered nor controlled Assurance of the safety quality and effi cacy of medicinal plants and herbal products has now become a key issue in industrialized and in developing countries Both the general consumer and healthcare professionals need up-to-date authoritative information on the safety and effi cacy of medicinal plants With the widespread use of TM as well as CAM and the rapid expansion of international herbal medicine markets the development of national policies and regulations on TMCAM has become an important concern for both health authorities and the public Providers of TMCAM other healthcare professionals and TMCAM consumers alike are calling for regulations that can ensure the safety of TMCAM therapies and products promote recognition of these systems and modalities and further defi ne their role in
Access this article onlineQuick Response Code Website
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DOI
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
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2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
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10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
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13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
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15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
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17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 235
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
modern healthcare systems National policies and regulations on TMCAM could ensure the safety quality and effi cacy of these therapies and products and function as important steps toward integrative healthcare systems However relatively few countries have developed policies and regulations on TMCAM so far Only 25 of WHOrsquos 191 countries have a national policy on TMCAM and only 64 countries regulate herbal medicines[1]
To assist countries in the development of TMCAM policies and regulations of herbal medicines WHO has published a series of technical guidelines and reviewed regulations on herbal medicines in the document ldquoRegulatory Situation of Herbal Medicines a Worldwide Reviewrdquo[2] The purpose of the document is to share national experience in formulating policies on traditional medicinal products introduce measures for their registration and regulation and facilitate information exchange on these subjects among Member States
In present review we have compiled name of various regulatory authorities made for herbal medicines in different countries with their major responsibilities and year of establishment which will defi nitely help the new researchers working in the fi eld of quality control and standardization of TMCAM
The role of herbal medicines in traditional healingThe pharmacological treatment of disease began long ago with the use of herbs[3] Methods of folk healing throughout the world commonly used herbs as part of their tradition Some of these traditions are briefl y described below providing some examples of the array of important healing practices around the world that used herbs for this purpose[4]
Traditional Chinese medicineTraditional Chinese medicine has been used by Chinese people from ancient times Although animal and mineral materials have
been used the primary source of remedies is botanical Of the more than 12000 items used by traditional healers about 500 are in common use[4] Botanical products are used only after some kind of processing which may include for example stir-frying or soaking in vinegar or wine In clinical practice traditional diagnosis may be followed by the prescription of a complex and often individualized remedy Traditional Chinese medicine is still in common use in China More than half the population regularly uses traditional remedies with the highest prevalence of use in rural areas About 5000 traditional remedies are available in China they account for approximately one-fi fth of the entire Chinese pharmaceutical market[4]
Japanese TMMany herbal remedies found their way from China into the Japanese systems of traditional healing Herbs native to Japan were classifi ed in the fi rst pharmacopoeia of Japanese TM in the ninth century[5]
Indian TMAyurveda is a medical system primarily practised in India that has been known for nearly 5000 years It includes diet and herbal remedies while emphasizing the body mind and spirit in disease prevention and treatment[6]
WHO GUIDELINES FOR HERBAL MEDICINES
These guidelines recognized the importance of herbal medicines to the health of many people throughout the world stating ldquoA few herbal medicines have withstood scientific testing but others are used simply for traditional reasons to protect restore or improve healthrdquo Most herbal medicines still need to be studied scientifi cally although the experience obtained from their traditional use over the years should not be ignored As there is not enough evidence produced by common scientifi c approaches to answer questions of safety and effi cacy about
Table 1 Different WHO guidelines with their major resolutions and year of establishmentWHO guidelines Major resolutions taken Year RefQuality control methods for medicinal plant materials
Emphasized the need to ensure the quality of medicinal plant products by using modern control techniques and include suitable standards and limits for contaminants are included
1998 [7]
WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems
Provide technical guidance on the principles of good pharmacovigilance and the inclusion of herbal medicines in existing national drug safety monitoring systems
2004 [8]
Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region
This guideline aims to facilitate the registration and regulation of herbal medicines by establishing the foundation for a harmonized regulatory standard to meet the common demands of the region
2003 [9]
General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine
Harmonize the use of certain accepted and important terms in TM summarize key issues for developing methodologies for research and evaluation of TM improve the quality and value of research in TM and provide appropriate evaluation methods to facilitate the regulation and registration of TMs
2000 [10]
National policy on TM and regulation of herbal medicines Report of a WHO global survey
Main objectives of this report are framing policy for safety effi cacy and quality of herbal medicines and its promoting rational use
2005 [1112]
WHO guidelines on good agricultural and collection practices for medicinal plants
Quality assurance of medicinal plant materials used as the source for herbal medicines and encourage and support the sustainable cultivation and collection of medicinal plants of good quality
2003 [13]
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
Q11
Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
236 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Australia Therapeutic Goods Act (Commonwealth of Australia 2001a)
The overall objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including medicines and medical devices available to the Australian public
1989 [1617]
Argentina Health Ministry of the Provincia de Buenos Aires
Regulation for registration and commercialization of medicinal plants
1993 [18]
Austria Herbal medicine regulation Law No541
Marketing authorizationsIssuing of license
1989 [19 20]
Belgium Ministry of Health Under the law proof of quality safety and effi cacy became an essential precondition for the registration of drugs
1995 [21-23]
Canada Natural Health Products Regulations
Ensure that the herbal medicinal plant product is safe under the recommended conditions of use without a prescription effective for the proposed claims and of high quality
2004 [24-27]
Chile Unidad de Medicina Tradicional Incorporating TM with proven effi cacy into health programs and of contributing to the establishment of their practice
1992 [28]
China The Drug Administration Law ofthe Peoplersquos Republic of China
Encourages the development of both modern and traditional drugs protects the resources of wild herbal drugs and promotes domestic cultivation of herbal drugs
1984 [18]
Colombia Ministry of Health Issuing of licenseDocumentation on the manufacturing process quality control and if necessary toxicity studies
1990 [29]
Denmark Danish Ministry of Health Order No 790
Proof of quality safety and effi cacy must be given a bibliographic application with respect to therapeutic use is accepted if it contains descriptions in the relevant scientifi c literature of Europe or North America
1992 [30 31]
Egypt National Applied Research Centre for Medicinal Plants and National Organization for Drug Control and Research
Medical health and nutrient content claims made by lawRules of GMP are implemented for herbal medicines
1995 [18]
Estonia Medicinal Products Act To maintain the documents concerning chemical pharmaceutical biological pharmacological-toxicological and clinical information of the herbal drugs
1996 [32]
Fiji Pharmacy and Poisons Act of Fiji Permits importation of TMs for use by ethnic communities 1994 [3334]Finland Administrative regulation 993
(Marketing Authorization 1993)Quality and manufacture of herbal remedies 1993 [35]
France French Medicines Agency Marketing authorizations [36] Germany Medicines Act of 24 August 1976 Herbal fi nished drugs have to comply with the same criteria for
quality safety and effi cacy as all other fi nished drugs 1976 [37-39]
Greece Ministry of Health Issuing of license documentation on the manufacturing process and toxicity studies
1994 [40]
Hungary Law on Public Health Chapter IV Section 104
Herbal drugs regulated as over the counter medicines for self-medication purposes and by law medical claims and health claims may be made
1996 [41]
India Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945
Regulate the import manufacture distribution and sale of drugs and cosmetics
1945 [42]
Indonesia Directorate of Traditional Drug Control
Production distribution and labeling of traditional drugs and licensing of traditional drugs and imported traditional drugs
1975 [18]
Ireland Guidelines for Application for Product Authorization of Herbal Products issued by National Drugs Advisory Board
Licensing of manufacturers and authorization of herbal products
1985 [4344]
Italy Italian Health Authority Grant licensed and ensure the quality safety and effi cacy 1981 [45]Japan Ministry of Health and Welfare Improve quality control of Kampo drugs 1972 [46]Korea The Ministry of Public Health and
Social AffairsRegulate and rule on the herbal medicines and their preparations
1969 [47-50]
Malaysia National Pharmaceutical Control Bureau Ministry of Health
Manufacturing import supply or sailing of the TMs [18]
Mali Traditional Medicine Department under the Ministry of Health
Postmarketing surveillance and adverse effect monitoring of herbal medicines
1968 [18]
Table 2 Contd
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
Q11
Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 237
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Table 2 Legal status of different countries for herbal drug regulationCountry Legal statuspolicy Major responsibilities Year of
establishmentRef
Mongolia Traditional Medicine Department under Mongolian National Medical University
Production development and investigation of TMs 1989 [51]
Nepal Department of Drug Administration under the Ministry of Health
Price approval safety effi cacy and quality of productsAuthorization for import export and distribution of the product and the mode of distribution and promotion
1996 [52]
New Zealand
Medicines Act of 1981 Control of active ingredients and excipients method of manufacture control tests of the fi nished product labeling stability etc
1981 [18]
Nicaragua The national pharmaceuticals law-292
Safety assessment 1998 [53]
Oman Ministry of Health Grant of license for manufacturing and import permission 1995 [54]Pakistan The Drugs Act of 1962 Controls the regulation of herbal medicines as regards
advertising and prevention of misuse1962 [18]
Portugal Portugal Drug Act Regulation of herbal medicines in the same laws as those covering conventional pharmaceuticals
1995 [55]
Qatar Ministry of Public Health By law medical health nutrient content and structurefunction claims may be made about herbal medicines
1990 [56]
Saudi Arabia
Ministry of Health KSA Medical health nutrient content and structurefunction claims may be made
1996 [18]
Singapore Traditional Chinese Medicine Practitioners Act
Marketing authorization and licensing of manufacturers 2000 [5758]
South Africa
Medicines Control Council (MCC) Dietary Supplement Health and Education Act of
Safety assessment requirements include traditional use without demonstrated harmful effects reference to documented scientifi c research on similar products and clinical data
1994 [2]
Spain The Spanish Medicinal Products Act No 25
Objective of the Act is to ensure the quality safety and effi cacy of therapeutic goods including herbal medicines
1990 [59 60]
Switzerland
The Swiss Agency for Therapeutic Products (Swissmedic) under Federal Department of Home Affairs
Marketing authorization And implementation of GMP rules 2002 [61]
Thailand The Drug Act BE 2510 Premarketing control licensing and registration process and postmarketing control by quality control analysis
1967 [18]
United Kingdom
Medicines and Healthcare products Regulatory Agency (MHRA) and Medicines Act 1968
Postmarketing surveillanceLicensed medicinal products require evidence of quality safety and effi cacy and are regulated by the Medicines Control Agency
1968 [62-66]
United States
Food Drug and Cosmetics ActDietary Supplement Health and Education Act
Ensuring that a dietary supplement is safe before it is marketed and the United States Food and Drug Administration is responsible for taking action against any unsafe dietary supplement product after it reaches the market
20001994
[67-70]
most of the herbal medicines now in use the rational use and further development of herbal medicines will be supported by further appropriate scientifi c studies of these products and thus the development of criteria for such studies In this regard WHO has issued guidelines for the assessment of herbal medicines These guidelines defi ned the basic criteria for the evaluation of quality safety and effi cacy of herbal medicines with the goal of assisting national regulatory authorities scientifi c organizations and manufacturers in assessing documentation submissions and dossiers in respect of such products
The below mentioned WHO guidelines [Table 1] stressed the need for assessment of effi cacy including the determination of pharmacological and clinical effects of the active ingredients cultivation and collection of the medicinal plants and labeling which includes a quantitative list of active ingredient dosage and contraindications
THE EUROPEAN UNION
The European Pharmacopoeia was created in 1964 its efforts have resulted in the creation of 83 monographs on herbal drugs that are used either in their natural state after desiccation or concentration or for the isolation of natural active ingredients The Association of the European Self-Medication Industry has carried out a study for the European Commission on herbal medicinal products in the European Union (EU) The following summary is taken from this report[14] The importance of herbal medicinal products varies from one country to another These products are not a homogeneous group In general they are either fully licensed medicinal products with effi cacy proven by clinical studies or by references to published scientifi c literature (in accordance with Article 48 a (ii) of Council Directive 6565EEC)[15] or are available
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
Q11
Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
238 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
as products with a more or less simplifi ed proof of effi cacy according to their national use Many Member States have these two categories but there are major discrepancies between the Member States in the classifi cation of individual herbal drug preparations and products into one of these categories as well as in the requirements for obtaining a marketing authorization According to Council Directive 6565EEC[15]
which has been implemented in national law in all Member States medicinal products require prior marketing approval before gaining access to the market In almost all Member States herbal medicinal products are considered as medicinal products and are in principle subject to the general regulations for medicines as laid down in the various national medicine laws In many cases a specifi c defi nition of herbal medicinal products is available which is in line with the EU Guideline ldquoQuality of Herbal Medicinal Productsrdquo This includes plants parts of plants and their preparations mostly presented with therapeutic or prophylactic claims Different categories of medicinal products containing plant preparations exist or are in the process of being created For instance draft legislation in Spain includes the defi nitions ldquoherbal medicinal productsrdquo and ldquophytotraditional productsrdquo The latter are not considered as ldquopharmaceutical specialtiesrdquo and are therefore not classifi ed as herbal medicinal products
Legal status of different countries for herbal drug regulationLegislative controls in respect of medicinal plants have not evolved around a structured control model There are different ways in which countries defi ne medicinal plants or herbs or products derived from them and countries have adopted various approaches to licensing dispensing manufacturing and trading to ensure their safety quality and effi cacy and due to these reasons herbal preparations varies from country to country In some phytomedicines are well established whereas in others they are regarded as food and therapeutic claims are not allowed This article follows a generalized template that includes regulatory authorities of various countries and their major responsibilities with year of establishment [Table 2]
CONCLUSION
The growth of the pharmaceutical industry and the unceasing development of new and more effective synthetic and biological medicinal products have not diminished the importance of medicinal plants in many societies On the contrary population growth in the developing world and increasing interest in the industrialized nations have greatly expanded the demand for medicinal plants themselves and the products derived from them Regulations in countries for the assessment of the quality safety and effi cacy of medicinal plants and the work of WHO and EU in supporting the preparation of model guidelines in this fi eld have been helpful in strengthening recognition of their role in health care It is hoped that assessment of these traditional
remedies could become the basis for a future classifi cation of herbal medicines as well as for evaluative studies on their effi cacy and safety and their potential use in national healthcare systems in different parts of the world
AKNOWLEDGEMENT
The authors acknowledge the University Grant Commission [F No 34-1312008 (SR)] New Delhi India for fi nancial support
REFERENCES
1 World Health Organization Research Guidelines for Evaluating the Safety and Effi cacy of Herbal Medicines Manila 1993
2 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review (WHOtrm981) Geneva 1998
3 Schulz V Haumlnsel R Tyler VE Rational Phytotherapy A Physicianrsquos Guide to Herbal Medicine 4th ed Berlin Springer 2001
4 Li L Opportunity and challenge of traditional Chinese medicine in face of the entrance to World Trade Organization Chin Inform trad Chin Med 200077-8
5 Saito H Regulation of herbal medicines in Japan Pharmacol Regul 200041515-9
6 Morgan K Medicine of the Gods Basic Principles of Ayurvedic Medicine 2002 Available from httpwwwcompulinkcoukmandrake ayurvedahtm [Last accessed on 2010 Jul 02]
7 World Health Organization Regulatory Situation of Herbal Medicines A Worldwide Review Geneva World Health Organization 1998
8 World Health Organization Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004
9 World Health Organization Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region 2003
10 World Health Organization General guidelines for methodologies on research and evaluation of traditional medicine Geneva WHO 2000
11 World Health Organization National policy on traditional medicine and regulation of herbal medicines Report of a WHO global survey 2005
12 World Health Organization Traditional Medicine Strategy 2002ndash2005
13 World Health Organization Guidelines on good agricultural and collection practices (GACP) for medicinal plants 2003
14 AESGP (Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public The Association of the European Self-Medication Industry) 1998
15 European Commission Council Directive 6565EEC on the approximation of provisions laid down by Law Regulation or Administrative Action relation to proprietary medicinal products Off J 196522369-73
16 Briggs DR The regulation of herbal medicines in Australia Toxicology 2002181-182565-70
17 Therapeutic Goods Administration Medicines Regulation and the TGA Woden ACT Australia 1999
18 Xiaorui Z Regulatory situation of herbal medicines A worldwide review Tradit Med Program 19981-45
19 Verordnung des Bundesministers fuumlr Gesundheit Sport und Konsumentenschutz mit der die Verordnung betreffend Erleichterungen bei der Zulassung bestimmter Arzneispezialitaumlten geaumlndert wird Bundesgesetzblatt fuumlr die
Q2
Q3
Q4
Q5
Q6
Q7
Q8
Q9
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Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
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Q13
Q14
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Q17
Q18
Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
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240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
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How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10 239
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Republik Oumlsterreich 19923912-5 20 Verordnung des Bundesministers fuumlr Gesundheit und
oumlffentlicher Dienst und des Bundesministers fuumlrwirtschaftliche Angelegenheiten vom 21 November 1989 betreffend die Abgabe und Kennzeichnung bestimmter Arzneimittel im Kleinverkauf (Abgrenzungsverordnung) Bundesgesetzblatt fuumlr die Republik Oumlsterreich 19894049-78
21 Sofi a Bulgaria Information letter of the Ministry of Health National Drug Institute dated 1996 Feb 07
22 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle directives agrave la constitution du dossier denregistrement des meacutedicaments agrave base de plantes Moniteur belge 19953103-9
23 Ministegravere de la Santeacute Publique et de lEnvironnement Circulaire ministeacuterielle nE 367 du 1989
24 Jordan SA Cunningham DG Marles RJ Assessment of herbal medicinal products Challenges and opportunities to increase 2 the knowledge base for safety assessment Toxicol Appl Pharmacol 2010243198-216
25 Johnson T Chinese medicine now part of primary care scene in BC CMAJ 20011641195
26 Sibbald B New federal offi ce will spend millions to regulate herbal remedies vitamins CMAJ 19991601355-7
27 Kozyrskyj A Herbal products in Canada How safe are they Can Fam Physician 199743697-702
28 Calixto JB Effi cacy safety quality control marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents) Braz J Med Biol Res 200033179-89
29 Ministerio de Salud de la Republica de Colombia resolucion Numero 1990
30 Bekendtgoslashrelse om naturlaeliggemidler Sundhedsministeriet Nr 1992790
31 NLN Regulatory Seminars in Quality Assessment of Natural Remedies NLN Publication No 40 Uppsala Nordic Council on Medicines 1996
32 Procedure for registration of medicinal products and approval of variations to the terms of registered medicinal products Estonia 1996
33 Bailey M Communication of the Ministry of Health Suva Fiji with World Health Organization 1996
34 The NSW Therapeutic Medicines Information Centre The uncertain world of herbal medication - a drug information viewpoint Drug Bull 199319
35 Commission Directive 91507EEC of 19 July 1991 modifying the Annex to Council Directive 75318EEC on the approximation of the laws of Member States relating to analytical pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products Offi cial Journal of the European Communities nE L 27032 of 26 Sept 1991
36 Castot A Djezzar S Deleau N Guillot B Efthymiou ML Drug surveillance of herbal medicines Theacuterapie 19975297-103
37 Kraft K Herbal medicine products and drug law Forsch Komplementaumlrmed 1999619-23
38 Sandberg F Corrigan D Natural remedies Their Origins and Uses New York Taylor and Francis 2001
39 Keller K Legal requirements for the use of phytopharmaceutical drugs in the Federal Republic of Germany J Ethnopharmacol 199132225-9
40 Minister of health providence and social insurance regulation Ankara 1994
41 Association Europeacuteenne des Speacutecialiteacutes Pharmaceutiques Grand Public (AESGP) editor Economic and Legal Framework for Non-Prescription Medicines in Europe Brussels AESGP
Q11
Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
Q21
1996 p 105-942 Drug and cosmetic act Government of India 194243 Morris JM Communication of the Irish Medicines Board with
World Health Organization 1996 44 Guidelines for Application for Product Authorization of Herbal
Products Dublin National Drugs Advisory Board 198545 Prodotti a base di piante medicinali Circolare n 1 (N
8007AG8254) Direzione Generale del Servizio Farmaceutico Divisione VII 1981
46 Eguchi K Hyodo I Saeki H Current status of cancer patientsrsquo perception of alternative medicine in Japan A preliminary cross-sectional survey Support Care Cancer 2000828-32
47 Choi DW Kim JH Cho SY Kim DH Chang SY Regulation and quality control of herbal drugs in Korea Toxicology 2002181-182581-6
48 Bonati A Guidelines for the chemical and biological assessment of herbals and herbal preparations UNIDO 19891-18
49 Korean Pharmacopoeia 7th ed Seoul Korea Medicine Publishers 1997
50 Korean Herbal Pharmacopoeia Korea Ministry of Health and Welfare 1987
51 Ministry of Health Traditional Mongolian Medicine Information sheet Mongolia 1996
52 Gewali MB Personal communication 1995 Nov 1653 Sotomayor U Traditional Medicine in Nicaragua and its
Integration into the Local Health Systems Lecture held at the Morris Arboretum Symposium Philadelphia 1993 Apr 19-21
54 Ministry of Health of the Sultanate of Oman Conditions to allow import of traditional drugs Muscat 1995
55 Farinha A Cachadinha M Algumas consideraccedilotildees sobre a Legislaccedilatildeo Portuguesa Fitoterapia LEF July 1994 no 2
56 World Health Organization Guidelines for the Assessment of Herbal Medicines (WHO Technical Report Series No 863) Geneva WHO 1996
57 World Health Organization Western Pacifi c Regional Offi ce (WPRO) 1996
58 Pharmaceutical Department of the Ministry of Health of Singapore Communication with WHO 1996 Mar 13
59 La Ley des Medicamento Madrid Art 42Ley 25199060 Orden de 3 de octubre de 1973 por la que se establece el registro
especial para preparados a base de especies vegetables medicinales Ministerio de la Gobernacioacuten BOE nE 247 de 15 de octubre de Madrid 1973
61 Mitteilungen der IKS IKS Monatsbericht Bern 19926345 62 Griffi n JP The evolution of human medicines control from a
national to an international perspective Adverse Drug React Toxicol Rev 19981719-50
63 Ministry of Agriculture Fisheries and Food (MAFF) Herb Legislation London Herb Society 1998
64 Mills SY The House of Lords report on complementary medicine A summary Complement Ther Med 2001934-9
65 Shaw D Risks or remedies Safety aspects of herbal remedies J R Soc Med 199891294-6
66 De Smet PA Should herbal medicine-like products be licensed as medicines BMJ 19953101023-4
67 Chang J Scientifi c evaluation of traditional Chinese medicine under DSHEA A conundrum Dietary Supplement Health and Education Act J Altern Complement Med 19995181-9
68 Angell M Kassirer JP Alternative medicine-the risks of untested and unregular remedies N Engl J Med 1998339839-41
69 Goldman SA Kennedy DL FDArsquos Medical Products Reporting
Q22
Q23
Q24
Q25
Q26
Q27
Q28
Q29
Q30
Q31
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared
240 Pharmacognosy Reviews | July-December 2011 | Vol 5 | Issue 10
Ajazuddin and Saraf Legal regulations of complementary and alternative medicines in different countries
Program A joint effort toward improved public health Postgrad Med 199810313-6
70 Food and Drug Administration Guidance for Industry Botanical Drug Products Washington DC Center for Drug Evaluation and Research 2000 Available from httpwwwfdagovcder guidanceindexhtm [Last accessed on 2010 Jul 02]
Authey Quary
Q1 Plz provide departmentQ2 Plz provide publication nameQ3 plz confi rm journal nameQ4 plz confi rmQ5 Plz provide publication name and cityand city Q6 Plz provide publication name and cityand city and cityand cityQ7 Plz provide publication name and cityand city and cityand cityQ8 Plz provide name of authors and confi rm journal nameQ9 Plz confi rm journal name and provide volume numberQ10 Plz provide in English translation and also provide volume numberQ11 Plz provide in English translation and also provide volume numberQ12 Plz provide in English translation and also provide volume numberQ13 Plz provide in english translationQ14 Plz confi rm journal nameQ15 Plz provide in English translationQ16 plz provide publication name And authors nameQ17 Plz provide journal name and volume number And confi rm titleQ18 Plz provide page numbers and authors nameQ19 plz provide publication nameQ20 plz provide name of authorsQ21 plz provide publication name and city and authors name Q22 plz provide journal name and volume number and page numberQ23 plz provide in english translationQ24 plz provide journal name and volume noQ25 Plz provide name of authorsQ26 plz provide publication nameQ27 plz provide publication nameQ28 Plz provide publication name and authors nameQ29 plz provide English translationQ30 Plz provide in English translationsQ31 Plz confi rm tilte
How to cite this Article
Source of Support University Grant Commission [F No 34-1312008 (SR)] New Delhi India Confl ict of Interest None declared