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DRUG DELIVERY »
Development of a New Delivery Modality Based on Oral-Soluble Postage Stamp Size Films
Zheng Lu, Reza Fassihi*
School of Pharmacy, TemtJie Umversrty, Plu/adelphro, PA
'(ormpondmg author: reta fossrlui}temple.edu
Lb I Ho •\ ll' \ \ I March 2016
Introduction
In recent years, many scientists In the pharmaceutical Industry are
focusing part of their research activity on the development and use
of oral strip technology (OST)'. Medicated oral strips can be used
for local effect2•1, rapid release and absorption as well as controlled
release systemic drug delivery via mucoadhesive principles•·6 • The
advantages of OST include the ease of administration especially for
pediatric and geriatric patient population who may have the difficulty
of swallowing larger oral dosage forms. It also offers an alternative
platform for molecules that undergo hepatic first-pass metabolism
and avoids the drug degradation and pre-systemic elimination
within the gastrointestinal tract7·8• Table 1 lists some commercially
approved oral strip products for transmucosa l drug delivery. However,
development of oral strip with high drug content uniformity, uniform
appearance and adequate physical and mucoadheslve strength
remains a challenge for pharmaceutical scientists especially when the
drug dose is high. Furthermore, lack of standardized test methods and
monographs in the US Pharmacopeia (USP) makes It more difficult to
develop and compare different oral strip products in terms of their
dissolution performance, formulation differences, excipient effects
and regulatory assessment.
Production of Medicated Oral Str ips
Oral strips are usually prepared by conventional casting methods
in which the solution or emulsion of the polymers, drug and other
exciplents Including plasticizers, sweeteners, surfactants, preservatives,
sa livary stimulating agents etc. are poured into a suitable mold and
allowed it to dry. This process usually consists of six steps including:
preparation of casting solution; deareation of the solution; transfer
of the prepared solution into an appropriate mold with defined
depth and volume; drying the deposited polymeric film; cutting the
- DRUG DELIVERY »
Ondansetron Rai>ldfilm• Labtec Gmbll Ondanse tron 4 mg and 8 mg Prevention of chemotherapy and radiation-Induced nausea and vomiting.
Oonezepll Rapldfltm• Labtec GmbH Oonepezll hyd•ochlo•lde 5 mg and 10 mg Treatmem of mild to moderately severe dementia or the
Alzheimer's tys>c
ChiOJasepttc• Relief St1ipsTM lnnot cn Inc Benzocaine l mg Occasiont~l minor irritat ion. pain. sore throat and sore mouth
Supp1essTM Cough st1ips with Oext•omothOiphan
lnnozen Inc Dexttomethorphan h)ldrobromlde 2.5 mg TempoJtully suppu~sses coughs due to minor throat and Uronchial Irr itation associa ted with cold Inhaled Irrit an ts.
Tliamlnlc TI1in Strlt» ' Cough & llunnyNosc
Novar tis OlphenhydrMllnc I ICI 12.5 rug J Tempowrlly ICiicves cough due to minor throat and bronchial irritation occurring wi th a cold. Temporarily relieves Itchy, watery
eyes cll le to hay rever.
Theraflu• Daytime Thin Strips Novarels Ocxtr(Hl)ethorphan 14.8 mg. Phc nylcptu inc HCI 10 mg Relieves n inal and sinus congC)tlon due to cold. Reduces cough.
Onsolis• BioOelivcry Science lntcmat lonal Fentanyl buccal soluble f1lm Management or breakthrough pal" In opioid-toiNant
cancer patients
j Gunavall' (but>rcnorphlno and naloxone buccal f1im)
BloOcl lvcry Science lntcrn il tlonnl Uuprenorphlrle 6 3 mg
Naloxone I mg
prepared oral film into the desired size; and packaging of the final
oral strip product. When manufacturing the oral strips using the
casting method, particular attention must be given to the rheological
properties of the casting solution, absence of entrapped air bubbles,
film uniformity and content uniformity in the final dosage form.
Oral films can also be prepared by using other technologies such as
direct compression and hot-melt extrusion (HME)9•10
. The advantages
of using the HME technique is that it avoids the use of water or
other organic solvents and therefore expedites the drying process.
However, it is undesirable for heat labile drugs and the mixing is less
homogeneous compared to preparation of a drug-polymer solution.
In-vitro Characterization of Medicated Oral Strips
Characterization of critical properties such as the mechanical strength,
drug content uniformity, dissolution rate and permeation rate
represent some of the major research areas in the design of oral strips.
Content uniformity is a major challenge associated with the
conventional solvent casting method. Historically production of films
have suffered from particle aggregation and non-uniformity due to the
large number of excipients used In their formulation including, soluble
polymers, surfactants, flavors, sweeteners, plasticizers, preservatives
and drugs. Yang et al. indicated that self-aggregation was one of the
main causes of poor uniformity and in particular the relatively long
drying time was found to facilitate intermolecular attractive forces,
convection forces, air bubbles and the like to form such aggregation".
The formed agglomerates randomly distribute inside the cast fi lm and
result in an inaccurate amount of active ingredient Inside each strip
after the cutting process. In order to obtain uniform oral strips, many
attempts have been made such as optimization of film composition,
addition of viscous agents such as gel formers or polyhydric
alcohols' ~· 11, use of controlled drying process for example radiation
drying". Furthermore other techniques for determining drug content
assay, such as X-ray d iffraction, and scanning electron microscopy
can be used to evaluate the content uniformity of oral strips.
28 I Hr•\'lt ' \\ I March 2016
Malntcuance treatment or oploid dcpc11dcnce
Non-aggregating strips are characterized as an amorphous state with
the absence of significant sharp peaks during X-ray diffraction (XRD)
analysis. A rough and uneven surface with lumps In the microscopic or
SEM images of oral strips Is an Indicator of self-aggregation and non
uniformly dispersed formulation.
The determination of properties of polymeric films including oral strips
is based on standard mechanical testing methods as presented in this
work using textural analyzer (Figure 1 )11• During the tensile testing,
the oral strip was mounted between two clamps and the stress
strain curve (or load-time profile) was recorded when the strips were
pulled by the top clamp at a fixed rate. From the stress-strain curve,
the tensile strength, percentage elongation at break and the elastic
modulus (also known as Young's modulus) are calculated.
Despite intensive work on oral strip technology, there is no official
standardized method or monograph in the US Pharmacopeia (USP)
for evaluating its "in vitro dissolution" behavior. Most of the studies
have used the paddle over disc method (similar to USP apparatus 5) to
assess the release of drug from the prepared films '0·". Briefly, the film
is fixed on a glass plate and is immersed in the dissolution medium
below the paddle and the paddle is rotated at a fixed rotation per
minute (rpm) speed. Nevertheless, in most of the studies the provision
Figure 1. Texture analyzer equipped with grips for measuring the mechanical properties of oral strip (left) and typical load-time
profile of oral strip under mechanical stress (right).
« DltUl; DEI.IVERY c.
2-side release 1-side release
XXXXXX)()(XXXXXXXXXXXXX mWI XXXXXXXXIOCXXJOOOOUCXXX melll
Side-view <-""" ..., ,...,..., :==== +- Ot.a rn lwnli)le) ... ""'"'""' XXXXXXXXXlOCXX.XXXX.XXXX me"' xxxxxxxxxxxxxxxxxxxxx ..,.,h
Top-view
Or.- fihh~l t pl.a\lk titm
Figure 2. Modified UPS Apparatus II with double mesh assembly used for dissolution testing of oral-soluble films and illustration of 2-sfde and 1 · side release design.
has been made such that the drug release occurs from a single side of
the strip. This is inconsistent with the real situation "in vivo" where the
drug release can happen from both sides of the oral strip. Therefore,
our lab is proposing a modified UPS Apparatus II with double mesh
assembly to be considered for d issolution testing of ora l-soluble
films. The double mesh design allows the free drug release from both
sides of the oral strip. It also allow allows an easy switch from 2-side
to 1-side release by simply incorporated another plastic film between
the bottom mesh and the oral strip. Th is design offers more flexibility
compared to other methods (Figure 2).
Experin1ental Section
Moteriols nnrf mellwds
In one of the studies, we developed a new postage stamp size oral
strip of water-soluble model drug tramadol HCI using the casting
method according to the formu la shown in Table 2. The aqueous
solutions of each component were thoroughly mixed with the help
of a glass mortar and pestle then poured into the glass/plastic molds
w ith defined depth and dried inside the hood for 14 hours. The
resultant films were cut into stamp size (2.5 cmx1.75 em) oral strips
having fi nal composition (w/w) of 21 .78% API (tramadol HCI), 4.95%
carbopol, 49.5% PEO, 4.95% HPMC, 3.96% glycerol, 9.9% mannitol/
Ingredient Formulation 1 Formulation 2 Function
Carbopol 4.95 4.95 Polymeric matrix
PEO N·80 49.5 49.5 Polymeric matrix
HPMCK4M 4.95 4.95 Vi~cm1s agcut
Glyce•ol 3.96 3.96 Plasuslzcr
Manrlitol 9.9 Sweetening agent
5o•bltol 9.9 Sweetcnmg agent
Citric acid 4.95 4.95 Saliva stimulating i'lgcnt
T•amadol HCI 21.78 21.78 Active ingredient
sorbitol and 4.95% citric acid in the dry form. The dissolution studies
of prepared stamp size oral strips were carried out using modified
UPS apparatus II (paddle with double mesh assembly) (Figure 2) at a
stirring speed of 25 rpm and 50 rpm in 500 ml simulated saliva (pH 6.8)
at 37 oc. The samples were withdrawn at predetermined time intervals
and the percentage dissolved of the drug was determined using a UV
spectrophotometer at 271 nm. The rheological properties of the films
such as tensile strengths, percent elongation, viscoelasticity, structural
recovery were evaluated using a computerized textural analyzer.
Results and Discussion
The resultant stamp-size oral films have an average weight of
0.08g and average thickness of 140 1Jm. On exposure to modified
dissolution testing, the oral strips quick ly hydrated and about 80% of
the drug was released within 15 minutes at a stirring speed of 25 and
50 rpm irrespective of the type of mesh device assembly used (i.e.
2-side or 1-side release) (Figures 3 and 4). More consistent and slower
release was apparent when only one side of the fi lm was exposed to
dissolution medium.
Textural analysis of the prepared oral strips (without tramadoi·HCI)
showed acceptable physica l properties with tensile strength around
• __ s=i
-·-"·~ •o.cn.Jtloh • ,,,,..,.....,a.rp.., , .•• ''~.--~~~~--~~
~-rt,,~ • ....,.,, .• * -rt. pw•I.Or""'· '·~
Figure 3. Dissolution profiles of tramadol-HCI oral strip (Formulation 1) using modified dissolution apparatus II
with Inserted double-mesh assembly at stirring speed of SO rpm and 25 rpm. Drug release was occurring from 2-side and 1·slde
of oral strip.
www.americanplmrrnaceu!icalrcvle.v.com I I ·:1 '\ 11 'II I 29
DRUG DEI.I VERY »
100
80
'2 60 >
~ i5 40 ~
20 --F1, paddle 50rpm, 1-slde -- F2, paddle 50rpm, 1-slde
0 0 5 10 16 20 26 30
Time (min)
Flgur~ 4. Comparison of dissolution rate of tramadoi-HCI from Formulation 1 and 2 when only one side of film was exposed.
Thickness (mm) 0.100± 0.0 14 0.087.1 0.007
I Tensile >!length (MPa) 5.6h0.77 5.61 :1. 0.56
I %Elongation at break 5.9710.68 8.16 .1 0.78
Clastic Modulus (MPa) 171.26 ± 24.68 162.18' 16.n
Work of Failure (KJ/m') 6.48 i 1.29 9. 11 ± 1.85
5.62 MPa, percent elongation at break of about 5.97% and 8.16%
under studied condition (Table 3).
Conclusion
This study highlights the importance of content uniformity and in vitro
characterization of oral strips using mechanical testing techniques and
proper dissolution methodology. As described in the experimental
section, a stamp-size oral-soluble fi lm with non-self-aggregating
characteristics was successfully developed with acceptable visco
elasticity, physical strength and release of ~80% of the drug within
1 5 minutes using a casting method. Due to the ease of administration
and avoidance of hepatic first-pass metabolism, oral strip technology
has been explored extensively during the last decades. The goal is to
overcome some of the disadvantages associated with conventional
oral drug delivery where drug and the dosage form is extensively
exposed to the milieu of the gastrointestinal tract with potential d rug
degradation, metabolism, slower onset effect and consequently lower
bioavallabi lity. Oral strips offer an alternative dosage form for patients
~0 I I:,'\ 1< '\\ I March 2016
having difficulty in swallowing of tablets or capsules and exhibit ease
of administration and improved patient compliance. The oral strip
technology is an ideal choice for administration of potent drugs used
to treat acute conditions where rapid onset of action Is required. The
Improvement of manufacturing processes and evaluation of oral strips
presented in this work Is expected to assist pharmaceutical scientists
to produce oral strips with precise dose, better content uniformity and
esthetically more attractive dosage forms for patients.
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conlrolled release, 139.2 (2009) 94·107.
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10. 10. M.A. Repka, K. Gutta, S. ProdduiUri, M. Munjal, 5.P. Stodghill, Characterization of cellulosic hot·melt cxlruded films containing lidocaine, Eur. J. Pharm. Biopharm. 59 (2005) 189- 196.
11. 1 1. R.K. Yang, R.C. Fuisz, G.l. Myers, et al., Thin film with non·self-aggregating uniform heterogeneity and drug delivery syslems made therefrom: U.S. Patenl 7,425,292. 2008·9-16.
12. 12. M. Horstmann, W.laux, S. Hungerbach. Rapidly disintegrating sheet-like presentations of mulliple dosage unils: U.S. Patent 5,629,003. 1997 ·5-13.
13. 13. H.G. Zerbe, J.H. Guo, A. Serino. Waler·soluble polymer; at least one member selected from the group consisting of a polyalcohol. a surfactant and a plasllcizer; at least one cosmetic or pharmaceutically ingredlenl; and a flavoring agent: U.S. Patenl S,948,430. 1999-9-7.
14. 14.l. Slevens-Figueroa, A. Bhakay, J.l. Jerez-Rozo, et al. Preparation and characterlzalion of hydroxypropyl methyl cellulose films containing stable B<S <lass II drug nanoparllcles for pharmaceullcal applications. International journal of pharmaceutics, 423.2 (2012) 496-508.
15. 15.l. Perioll, V. Ambrogi, F. Angelici, M. Ricci, S. Giovagnoli, M. Capuccella, C. Rossi, Developmenl of mucoadhesive palches for buccal administrallon of Ibuprofen, J. Control. Release 99 (2004) 73-82.
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