RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

ANNEXURE II

1 Name of the candidate and

address

N.V.RAMARAJU GEDELASivagopalapuramNear ganganamma templeThengellamudhiEluru A.P

2 Name of the Institution ACHARYA AND B.M. REDDY

COLLEGE OF PHARMACY, Chikkabanavara Post ,Hesaraghatta Main Road , Soladevanahalli,Bangalore-560 090.

3 Course of the study and subject

M. Pharmacy(Pharmaceutics)

4 Date of admission May-2007

5 TITLE OF THE PROJECT:-

“FORMULATION AND EVALUATION OF

ZIDOVUDINE MICROSPHERES

6

6.1

BRIEF RESUME OF INTENDED WORK:-system

NEED FOR THE STUDY:-

AZT is an antiretroviral drug, specifically a nucleoside reverse transcriptase inhibitor. It is used to treat HIV, a retrovirus.  Retroviruses use the genetic material in the body’s cells to produce more virus which can infect other cells.

Zidovudine was the first drug approved for the treatment of AIDS and HIV infection. Jerome Horwitz of Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine first synthesized AZT in 1964, under a US National Institutes of Health (NIH) grant. It was originally intended to treat cancer, but failed to show efficacy and had an unacceptably high side effect profile. The drug then faded from view until February 1985, when Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan, three scientists in the National Cancer Institute (NCI), collaborating with Janet Rideout and several other scientists at Burroughs Wellcome (now GlaxoSmithKline), started working on it as an AIDS drug. After showing that this drug was an effective agent against HIV in vitro, the team conducted the initial clinical trial that provided evidence that it could increase CD4 counts in AIDS patients.

AZT does not destroy the HIV infection, but only delays the progression of the disease and the replication of virus, even at very high doses. During prolonged AZT treatment HIV has the ability to gain an increased resistance to AZT by mutation of the reverse transcriptase. A study showed that AZT could not impede the resumption of virus production, and eventually cells treated with AZT produced viruses as much as the untreated cells. So as to slow the development of resistance, it is generally recommended that AZT be given in combination with another reverse transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor.

Like other reverse transcriptase inhibitors, AZT works by inhibiting the action of reverse transcriptase, the enzyme that HIV uses to make a DNA copy of its RNA. The viral double-stranded DNA is subsequently spliced into the DNA of a target cell, where it is called a provirus.[8][9][10]

The azido group increases the lipophilic nature of AZT, allowing it to cross cell membranes easily by diffusion and thereby also to cross the blood-brain barrier. Cellular enzymes convert AZT into the effective 5'-triphosphate form. Studies have shown that the termination of the formed DNA chains is the specific

factor in the inhibitory effect.

The triphosphate form also has some ability to inhibit cellular DNA polymerase, which is used by normal cells as part of cell division.[11][12][13] However, AZT has a 100- to 300-fold greater affinity for the HIV reverse transcriptase, as compared to the human DNA polymerase, accounting for its selective antiviral activity.[14] A special kind of cellular DNA polymerase that replicates the DNA in mitochondria is relatively more sensitive to inhibition by AZT, and this accounts for certain toxicities such as damage to cardiac and other muscles (also called myositis)

AZT interferes with the life cycle of HIV to stop it from producing more virus.  Specifically, AZT ties up the reverse transcriptase enzyme so it cannot build the genetic material needed to make more virus and infect more cells.

It is extremely important that you take AZT and your other

antiretroviral medications exactly as directed.  You should set up a system that

will help you remember to take your medicines so that you do not miss any

doses.  If you miss a dose, take it as soon as possible; however, if you skip a

dose, do not take two doses at once.  Do not stop taking the medication for

anyssss reason at any time unless you are directed to do so by your study

clinician.  If you are unable to continue taking your medication due to side

effects, you should contact your study clinician immediately.From the last few

decades, a great deal of research work has been devoted to the

development of site specific drug delivery systems which offer several

benefits over the traditional drug therapies. The principal goal of the site

specific delivery is to delivery the drug in the specific organ of body. The

therapeutic advantages of targeting the drug to the diseased organ include

reduced incidence of adverse side effects, lower conventional dose and

delivery of drug as close as possible to the target site.1

6.2

REVIEW OF LITERATURE:-

T. Shibashi et al developed a system was designed by imparting a timed-release

function and a pH-sensing function to a hard gelatin capsule for colon-targeted

delivery of drugs. The technical characteristics of the system are to contain an

organic acid together with an active ingredient in a capsule coated with a three-

layered film consisting of an acid-soluble polymer, a water-soluble polymer, and

an enteric polymer. As a result, it was found that: (1) various organic acids can

be used for this system; (2) a predictable timed-release mechanism of a drug can

be attained by adjusting the thickness of the Eudragit layer; and (3) the outer

enteric coating with HPMC provided acceptable acid-resistibility. All these

results suggested that this approach can provide a useful and practical means for

colon-targeted delivery of drugs4.

A. Sindhu et al developed Modified Pulsincap dosage of Metronidazole to target

drug release in the colon. Bodies of hard gelatin capsules were made insoluble

by treating it with formaldehyde and keeping the caps as such. Drug pellets

prepared by extrusion-spheronization method incorporated into the specialized

capsule shells and plugged with polymers guar gum,

hydroxypropylmethylcellulose 10K, carboxymethylcellulose sodium and

sodium alginate with different concentration. The filled capsule were coated

with 5% cellulose acetate phthalate to prevent variable gastric emptying. The

capsule was assessed by in vitro drug release studies in different buffer pH. The

results indicated that significant drug release occurred only after 5 h from the

start of experiment. Thus, Metronidazole could be successfully colon targeted

by the use of the modified Pulsincap, thereby reducing systemic side effects5.

Y.S.R. Krishnaiah et al developed colon targeted drug delivery system for

Albendazole using guar gum as a carrier. Matrix tablets containing various

proportions of guar gum were prepared by wet granulation technique using

starch paste as a binder. Evaluation &In vitro drug release studies were

conducted. The amount of Albendazole released from the marix tablets at

different time intervals was estimated by HPLC method. The dissolution studies

were also done. The result of the study show that matrix tablets containing either

10% or 20% of guar gum are most likely to provide targeting of Albendazole

showed no change either in physical appearance, drug content or in dissolution

pattern after storage at 40/75 %RH for 6month. Differential scanning

calorimetry indicated no possibility of interaction between Albendazole and

guar gum6.

Y.S.R. Krishnaiah et al developed for site-specific delivery of 5-fluorouracil

to the colon without the drug being released in the stomach or small intestine

using guar gum as a carrier. Fast-disintegrating 5-fluorouracil core tablets were

compression coated with 60%, 70% and 80% of guar gum, and were subjected

to in vitro drug release studies. The results showed that compression-coated

tablets containing 80% of guar gum are most likely to provide targeting of 5-

fluorouracil for local action in the colon, since they released only 2.38% of the

drug in the physiological environment of the stomach and small intestine7.

S.K. Lanjhiyana et al developed a Time dependent Site specific delivery of

Piroxicam into colon which is used in inflammatory bowel diseases. Dissolution

studies demonstrate that polymeric coated capsule were gastro-resistant for an

average time of 5 to 6 h post dose was found to be dependent on the polymeric

coating layers of HPMC and Eudragit l-100 and on the concentration of guar

gum, which is highly susceptible to colonic microfloras. The capsules having

optimized 30% of guar gum and polymeric coating ratios with and without 4%

rat caecal in PBS pH 7.4 suggest the susceptibility of polymers to the colonic

microfloras. No change in physical appearance, content uniformity and in

stability studies. Thus, Piroxicam could be successfully colon targeted by the

use of the modified Pulsincap8.

V.S. Mastiholimath et al developed an oral colon specific Pulsatile device to

achieve Site specific release of Theophylline. Here the insoluble hard gelatin

capsule body, filled with Eudragit microcapsule of Theophylline and sealed with

a hydrogel plug. The entire device was enteric coated, so that the variability in

gastric emptying time can be overcome and a colon-specific release can be

achieved. The Theophylline microcapsule and varying polymer ratio evaluated

for the particle size, drug content and in vitro release profile and from the

obtained result; one better formulation was selected for further fabrication of

pulsatile capsule. Different Hydrogel polymer were used as plug, to maintain

suitable lag period and it was found that the drug release was controlled by the

proportion of polymers used. Then the gamma scintigraphic study done for the

release of the drug in lower parts of GIT. The results gives the successful

chronotherapeutic drug delivery9.

A. Sindhu et al developed a Time dependent Modified Pulsincap that would

ensure chronotherapeutic delivery of Diclofenac sodium in the colon for the

rheumatoid arthritis. Bodies of hard gelatin capsule made insoluble and drug

pellets equivalent to 100mg were filled into the treated capsule shells, plugged

with hydrogel polymers HPMC, HPC and Sodium Alginate at different

concentration and enteric coated with 5% cellulose acetate phthalate. The

formulation were assayed to determine the drug content, invitro drug release

studies and the accelerated stability studies carried out for three months as per

ICH guidelines proved that the formulations were stable and thus Diclofenac

Sodium could be successfully given for colon targeted by modified pulsincap

capsule10.

Y.S.R. Krishnaiah et al developed in vivo performance of guar gum-based

colon-targeted tablets of Ornidazole in comparison with an immediate release

tablet of Ornidazole in six healthy human volunteers was investigated for which

a cross over design was followed. The immediate release tablets of Ornidazole

produced peak plasma concentration (Cmax of 2171.33+/-278.15 ng/ml) at

2.91+/-0.14 h (Tmax) whereas colon-targeted tablets produced peak plasma

concentration (Cmax of 1716.66+/-125.83 ng/ml) at 11.91+/-0.14 h. The

delayed Tmax, decreased Cmax, and decreased ka of Ornidazole from guar

gum-based colon-targeted Ornidazole tablets, in comparison with the immediate

tablets, indicated that the drug was not released in stomach and small intestine,

but targeted to colon. Slow absorption of Ornidazole from the less absorptive

colon might result in the availability of drug for local action in the colon11.

N.E. Stevens Howard et al developed evaluation of Dofetilide Pulsincap

delivery to the human GI tract. In these studies the effects of the degree of

dispersion versus the site of dispersion could not be ascertained; nevertheless the

scitigraphic analysis demonstrated good in vitro-in vivo correlation for time of

release from Pulsincap preparation. In scinti graphic analysis, the time of gastric

emptying, arrival at the ileocaecal junction and entry into colon were recorded.

The time of capsule opening, as determined by spreading of radiolabel in the GI

tract content, was determined by examination of the scintiscans.

Pharmacokinetic parameter values and elimination T1/2 from the solution dose

of Dofetilide were determined by using software WinNonlin Version 312.

A. Mohamad et al developed a rupturable, capsule-based Pulsatile drug

delivery system with pH-independent properties prepared using aqueous

coating. The drug release is induced by rupturing of top-coating, resulting by

expanding of swellable layer upon water penetration through the top-coating.

Here we determine drug release and lag time,sewlling volume, swelling energy,

mechanical properties of polymer films. The above experiment gives successful

result13.

6.3OBJECTIVE OF THE STUDY:-

The present study is planned with the following objectives:

1. Drug-Excipient compatibility studies.

2. Formaldehyde treatment of capsule bodies.

3. Selection of different swellable polymers for the hydrogel plug. The

concentration and selection of hydrogels is such that it takes a particular time

period (small intestinal transit time of 3-4 h) to be ejected out and release the

drug in the colon.

4. Formulation of controlled release Etoricoxib a Modified Pulsincap capsule

for targeting colon.

5. Evaluate the formulated dosage form by physicochemical characterization

and in vitro release studies.

6. Carry out short term stability studies on the most satisfactory formulation as

per ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH).

7

(i) 7.1

MATERIALS & METHODS:-

(ii) SOURCE OF DATA:-

1. Review of literature from:

a) Journal such as

Indian Journal of Pharmaceutical Sciences

European Journal of Pharmaceutical Sciences

Journal of Controlled Release

International Journal of Pharmaceutical Sciences

Drug Development and Industrial Pharmacy

Indian Drugs

b) Word wide web.

c) J-Gate@Helinet

2. Laboratory based studies.

7.2 METHOD OF COLLECTION OF DATA:-.

1) Preparation of the colon targeted time and pH dependent Aceclofenac

Pulsincap capsule using polymers like guar gum, HPMC, CMC, sodium

alginate with different concentration.

2) Drug-Excipient compatibility studies by IR/DSC.

3) Characterization of formaldehyde treated empty capsule for the following :

Average Capsule length before and after formaldehyde treatment.

Average diameter of capsule body before and after formaldehyde

treatment.

Average length of capsule body before and after formaldehyde

treatment.

4) Solubility studies of the treated Capsule.

5) Qualitative test for free formaldehyde.

6) Thickness of coating material and Weight Variation studies.

7) Drug release study using dissolution apparatus in simulated gastric and

intestinal

buffers for 24 hours.

8) To carry out short term stability studies on the most satisfactory formulation

as per

ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH).

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR

INVESTIGATION TO BE CONDUCTED ON PATIENT OR OTHER

HUMANS OR ANIMALS?

“NO”

7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR

INSTITUTION IN CASE OF 7.3?

“NOT APPLICABLE”

a) 8b)c) LIST OF REFERENCES:-

1. Sinha VR, Bhinge JR. Platform Technologies in colon Delivery. Pharma

Buzz 2006; 1(5): 13-15.

2. Kinget R, Kalala W, Vervoort L, Mooter GV. Colonic drug targeting. J.

Drug Targeting 1998; 6: 129–149.

3. P. Curtis Sean, B. Bockow, F. Chester, S. Reicin Alise. Etoricoxib in the treatment

of osteoarthritis over 52-weeks: a double blind, active-comparator controlled trial.

BMC Musculoskelet Disord. 2005; 6:58.

4. Ishibashi T, Hatano H, Kobayashi M, Mizobe M, Yoshino H. Design and

evaluation of a new capsule-type dosage form for colon-targeted delivery of

drugs. Int. J. of Pharm.1998; 168(1): 31-40.

5. Abraham Sindhu, Srinath MS. Development of modified pulsincap drug

delivery system of metronidazole for drug targeting. Indian J Pharm Sci

2007; 69: 24-27.

6. Y.S.R. Krishnaiah, K.Latha, L.Nageshwara rao, R.S.Karthikeya, P.Bhasker

and V.Satyanarayan. Development of colon targeted oral guar gum matrix

tablets of Albendazole for the treatment of Helminthiasis, Indian J Pharm

Sci 2003; 65(4): 378-385.

7. Y.S.R. Krishnaiah, Satyanarayana V, DineshKumar B, Karthikeyan RS. In

vitro drug release studies on guar gum-based colon targeted oral drug

delivery systems of 5-fluorouracil. Eur J Pharm Sci. 2002; 16(3): 185-192.

8. S.K. Lanjhiyana, G.P. Agrawal, J.S. Dangi, S. Lanjhiyana. Preparation and in-vitro

drug release study of Piroxicam from modified pulsincap capsule. Indian Drugs

44(3) 2007.

9. V. S. Mastiholimath, P. M. Dandagi, S. Samata Jain, A. P. Gadad, A. R. Kulkarni.

Time and pH dependent colon specific, pulsatile delivery of theophylline for

nocturnal asthma Int. J. of Pharm. 328 (2007) 49-56.

10. A. Sindhu, S.Bharath, B. V. Basavaraj, R. Deveswaran. Modified pulsincap drug

delivery system of Diclofenac sodium. The Pharma Review Apr-May 2007,

Kongposh Publication Pvt. Ltd, New Delhi, India.

11. Y.S.R. Krishnaiah, Muzib YI, Rao GS, Bhaskar P, Satyanarayana V.

Studies on the development of colon targeted oral drug delivery

systems for ornidazole in the treatment of amoebiasis. Drug Deliv.

2003; 10 (2): 111-117.

12. N. E. Stevens Howard, G. Wilson Clive, G. Welling Peter, S. Binns Julie, R. Wicks

Steve. Evaluation of pulsincap to provide regional delivery of Dofetilide to the

human GI tract. Int. J. of Pharm. 236 (2002) 27-34.

13. A. Mohamad, A. Dashevsky. pH-independent pulsatile drug delivery system based

on hard gelatin capsule and coated with aqueous dispersion Aquacoat. Eur. J

Pharm. & Biopharma. Oct 2006; 64(2): 173-179.

9 Signature of the candidate:

10 Remarks of the Guide: Recommended

11 Name and Designation of:

11.1 Institutional Guide: DR. ROOPA KARKIProfessor & HODDept. of Industrial pharmacyAcharya and B.M. Reddy College of Pharmacy, Chikkabanavara post Hesaraghatta Main Road, Soladevanahalli,Bangalore-560 090

11.2 Signature:

11.3 Co-Guide:

11.4 Signature:

11.5 Head of the Department: Dr. ROOPA KARKI Professor & HODDept. Of Industrial pharmacyAcharya and B.M. Reddy College of Pharmacy, Chikkabanavara post Hesaraghatta Main Road, Soladevanahalli,Bangalore-560 090

11.6 Signature

12 12.1 Remarks of the Principal Recommended.

12.2 Signature (iii) Prof. GOLI DIVAKAR(iv) Principal

ACHARYA & B.M.REDDY COLLEGE OF PHARMACY,SOLADEVANAHALLI,HESARAGHATTA MAIN ROAD,BANGALORE-90.