“FORMULATION AND EVALUATION OF SUSTAINED RELEASE

TABLETS OF AN ANTIRETROVIRAL DRUG ZIDOVUDINE”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

PATEL VAIDEHI HASHITKUMAR,

I Year M. PHARM,

DEPARTMENT OF PHARMACEUTICS,

NARGUND COLLEGE OF PHARMACY,

BANGALORE- 85. KARNATAKA.

2013-2015.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR PG DISSERTATION

1. NAME OF THE CANDIDATE

& ADDRESS (IN BLOCK

LETTERS)

PATEL VAIDEHI HASHITKUMAR.

NARGUND COLLEGE OF PHARMACY,

DATTATREYA NAGAR, II-MAIN,

100 FT RING ROAD,BSK 3rd STAGE

BANGALORE-560085

2. NAME OF THE INSTITUTION NARGUND COLLEGE OF PHARMACY,

DATTATREYA NAGAR, II-MAIN,

100 FT RING ROAD,BSK 3rd STAGE

BANGALORE-560085

3. COURSE OF STUDY AND

SUBJECT

MASTER OF PHARMACY IN

PHARMACEUTICS

4. DATE OF ADMISSION TO

COURSE14TH AUG 2013

5. TITLE OF THE TOPIC “FORMULATION AND EVALUATION OF

SUSTAINED RELEASE TABLETS OF AN

ANTIRETROVIRAL DRUG

ZIDOVUDINE’’

6 BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR THE STUDY :-

Oral drug delivery is the most preferred and convenient option as the oral

route provides maximum active surface area among all the drug delivery systems

for administration of various drugs. The attractiveness of these dosage forms is

due to awareness to toxicity and ineffectiveness of drugs when administered by

oral conventional method in the form of tablets and capsules. Usually

conventional dosage form produces wide range of fluctuation in drug

concentration in the blood stream and tissues with consequent undesirable toxicity

and poor efficiency. The maintenance of concentration of drug in plasma within

therapeutic index is very critical for effective treatment.1,2

Rational for Extended Release Pharmaceuticals:

Some drugs are inherently long lasting and require only once a day oral

dosing to sustain adequate drug blood levels and the desired therapeutic effect.

These drugs are formulated in the conventional manner in the form of immediate

release dosage forms. However, many other drugs are not inherently long lasting

and require multiple daily dosing to achieve the desired therapeutic results.

Multiple daily dosing is inconvenient for the patient and can result in missed

doses, made up doses and non compliance with the regimen. When conventional

immediate-release dosage forms are taken on schedule and more than once daily,

they cause sequential therapeutic blood level peaks and valleys (troughs)

associated with the administration of each dose. However, when doses are not

administered on schedule, the resulting peaks and valleys reflect less than

optimum drug therapy. For example, if doses are administered too frequently,

minimum toxic concentrations of drug may be reached, resulting in toxic side

effects. If doses are missed, periods of sub therapeutic drug blood levels or those

below the minimum effective concentration may result, with no benefit to the

patient. Extended-release tablets and capsules are commonly taken only once or

twice daily, compared to their counterpart conventional forms which may have to

be taken three or four times daily to achieve the same therapeutic effect.

Typically, extended release products provide an immediate release of drug that

promptly produces the desired therapeutic effect, followed by gradual release of

additional amounts of drug to maintain this effect over a predetermined period.

The sustained plasma drug levels provided by extended release products often at

times eliminate the need for night dosing which benefits not only the patient but

also the caregiver.3

The advantage of administering a single dose of a drug that is released over an

extended period of time to maintain a near – constant or uniform blood level of a

drug often translates in to better patient compliance, as well as enhanced clinical

efficacy of the drug for its intended use.

Sustained release, prolonged release, modified release, extended release

or depot formulations are terms used to identify drug delivery systems that are

designed to achieve or extend therapeutic effect by continuously releasing

medication over an extended period of time after administration of single dose.

The goal in designing sustained delivery system is to reduce the frequency of

dosing or to increase effectiveness of the drug by localization at the site of action,

reducing the dose required or providing uniform drug delivery. So, sustained

release dosage form is a dosage form that release one or more drugs continuously

in a predetermined pattern for a fixed period of time, either systemically or to a

specified target organ.3

Sustained release dosage forms provide a better control of plasma drug

levels, less dosage frequency, less side effects, increased efficacy and constant

delivery.1

The Following are the Rationale for Developing SR Matrix DDS

To extend the duration of action of the drug

To reduce the frequency of dosing

To minimize the fluctuations in plasma level

Improved drug utilization less adverse effect

Advantages of SR matrix DDS

The frequency of drug administration is reduced

Patient compliance can be improved

Drug administration can be made more convenient as well

The blood level oscillation characteristic of multiple dosing of

conventional dosage form is reduced

Better control of drug absorption can be attained, since the high

blood level peaks that may be observed after administration of a

dose of a high availability drug can be reduced.

The characteristic blood level variations due to multiple dosing of

conventional dosage forms can be reduced.

The total amount of drug administered can be reduced, thus

• Maximizing availability with minimum dose

• Minimize or eliminate local side effects

• Minimize or eliminate systemic side effects

• Minimize drug accumulation with chronic dosing

Safety margins of high potency drug can be increased and the

incidence of both local and synthetic adverse side effects can be

reduced in sensitive patients.

Improve efficiency in treatment

• Cure or control condition more promptly

• Improve control of condition

• Improve bioavailability of some drug

• Make use of special effects e.g. sustained release aspirin for

morning relief of arthritis by dosing before bed-time.

Economy

Disadvantages of SR matrix DDS

Probability of dose dumping

Reduced potential for dose adjustment

Cost of single unit higher than conventional dosage forms.

Increase potential for first pass metabolism.

Requirement for additional patient education for proper medication.

Decreased systemic availability in comparison to immediate release

conventional dosage forms.

Poor in vitro and in vivo correlations.4

More than twenty years after the first clinical evidence of acquired

immunodeficiency syndrome (AIDS) was reported it has become one of the most

devastating diseases human kind has ever faced. HIV/AIDS has become the

fourth largest cause of death worldwild.5

HIV:

Human Infects men, women, and children regardless of

Race or Age.

Immunodeficiency Destroys the human body’s natural ability to

fight infection.

Virus Small, infectious agent that reproduces within a

person.

HIV is a virus which gradually damages the body’s immune system and eventually

causes AIDS. The human body is equipped with CD4 cells, also called helper T

cells, which defend the body against viruses and bacteria. HIV damages the

immune system by attacking and entering these cells. Once inside the cell, the

virus reproduce and then move on to attack other helper T cells and repeat the

process. As more helper T cells are over taken, the body’s ability to fight any

illness decreases.

AIDS:

Acquired A condition one is not born within.

Immune deficiency An immune system that cannot fight off infections.

Syndrome Signs and symptoms that occur together and

characterize a particular illness.

When one’s immune system is damaged, then the body cannot fight

“opportunistic” infections. The most common opportunistic infections include

tuberculosis, pneumonia, skin cancer, meningitis, thrush, herpes, and bacterial

infections.6,7

Anti retroviral class of drug includes: Nucleoside Reverse Transcriptase

Inhibitors (NRTIs) like Zidovudine, Azidothymidine, Abacavir, Lamivudine,

Emtricitabine etc. Amongst all Zidovudine is the first anti HIV drug approved for

clinical use and is widely used for treatment of AIDS either alone or in

combination with other antiviral agents. However, the main limitation to

therapeutic effectiveness of Zidovudine is its dose-dependent hematological

toxicity, short biological half-life, and poor bioavailability.8 Treatment of AIDS

using conventional formulations of Zidovudine is found to have many drawbacks

such as adverse side effects due to accumulation of drug in multi-dose therapy,

poor patient compliance7 and high cost. So, sustained release formulations can

overcome some of these problems associated with the conventional formulations.

The drug is freely soluble at any pH, hence judicious selection of release retarding

excipients is necessary for achieving constant in vivo release.9

6.2 REVIEW OF LITERATURE:-

Samal et al. developed oral sustained release matrix tablets of an

antiretroviral drug, zidovudine. Matrix tablets were prepared by wet

granulation method using various proportions of hydrophilic polymers like

Sodium CMC, HPMC, Eudragit‐L155, & Xanthan gum along or in

combination with hydrophobic polymer ethyl cellulose. The release kinetics

was analyzed using zero order, first order, Higuchi and Hixson Crowell model.

From this study it was concluded that presence of sodium CMC gives zero‐order release kinetics and the linearity ranges from 0.990 to 0.996. It has also

good drug entrapment efficiency ranging from 96 to 106% of drug.

Formulation containing sodium CMC with Xanthan gum and EC gives

sustained release for drug more than 12hrs.10

Atul Kuksal et al., prepared extended-release matrix tablets of anti

retroviral drug, zidovudine using hydrophilic polymers Eudragit RLPO and

RSPO alone or in combination with hydrophobic polymer Ethyl cellulose.

The in-vitro drug release study revealed that either Eduragit preparation was

able to sustain the drug release only for 6 hours (94.3% ± 4.5%release).

Combining Eudragit with ethyl cellulose sustained the drug release for 12

hours (88.1% ± 4.1% release). 11

Patel Sunilkumar et al., formulated sustained release matrix of NSAID

ibuprofen by using matrix polymer HPMC and ethyl cellulose alone and in

combination. Drug release study was carried out using BP apparatus 2 in pH

7 buffer for 12 hr at 1 hr sampling interval. The results of dissolution study

concluded that the release of drug from matrix prepared from different ratios

of both HPMC and EC gets more retarded than from HPMC and EC alone.12

Subramaniam Kannan et al., developed sustained release tablets of

NSAID, aceclofenac (200mg) by wet granulation using hydrophilic polymer

like Hydroxy propyl methyl cellulose K -100. They showed the drug release

from optimized formulations was extended for a period of 24 hrs. The

kinetic treatment of selected formulations showed that the release of drug

follows zero order models. This study indicated the suitability of hydrophilic

polymers in the preparation of matrix based sustained release formulations

of NSAID.13

SC Basak et al., prepared Monolithic matrix tablets of ambroxol

hydrochloride, formulated as sustained release tablets employing Hydroxy

propyl methyl cellulose polymer by direct compression process. The results

of dissolution studies indicated that formulation containing drug to polymer

in the ratio of 1:1.47, as the successful formulation exhibiting drug release

pattern very close to theoretical release profile. A decrease in release

kinetics of the drug was observed on increasing polymer ratio. The

mechanism of drug release from optimized formulation was diffusion

coupled with erosion (anomalous).14

Deepika V et al., formulated the sustained release matrix tablets of an anti

retroviral drug, zidovudine. In this the sustained release matrix tablets were

prepared by wet granulation method by using hydrophilic polymers like

HPMC, SCMC and Na Alginate. The optimized formulation was further

modified using different hydrophobic polymers as granulating agents, such

as PVP, Eudragit RL100 and Ethyl cellulose to control the drug release.

They found that the hydrophilic matrix of HPMC alone could not control the

antiretroviral drug release effectively for 12 hours. Kinetic treatment to the

in vitro release data revealed that the drug release followed first order

release and mechanism of drug release is by Non-fickian transport.15

Mohd Abdul Hadi et al., prepared zidovudine controlled release beads by

ionotropic gelation method, using sodium alginate containing KHCO3 as the

gas-forming agent. The kinetic studies revealed that the drug was released

by zero-order kinetics. It was concluded that the floating beads designed for

the gastro retentive dosage form could be suitable for controlled drug

delivery.16

Kar RK et al., formulated and evaluated oral controlled release matrix

tablets of zidovudine by direct compression method using various proportion

of hydrophilic polymer along or in combination with hydrophobic polymer.

Dissolution study revealed that either Eudragit RS100 or RL100 10%, 20%

w/w of tablet preparations were able to sustain the drug release up to 9

hours, but 30%, 40% as well as EC combination with 20% and 25% w/w of

Eudragit RS100 and RL100 were able to sustaining the drug release for 12

hour.17

Punna RR et al., designed lamivudine (LMV) oral controlled release

matrix tablets using Hydroxypropyl methylcellulose as a retardant polymer

and showed good extension release of LMV and overcome the

disadvantages of conventional tablets of LMV.18

Evelyn O et al., investigated the effect of ethyl cellulose and 6 types of

HPMC (Methocel K100M, K100MPRCR, K15MPRCR, K4MCR) on

release profile of theophylline from matrix tablets was evaluated. Tablets

were prepared either by wet granulation method or direct compression

technique. Drug dissolution tests showed that formulations with 15% of

Methocel K4MPR, 15% of Methocel K4MPRCR and 30% of Ethocel

N10STD, obtained by direct compression method, compiled with official

specifications, in terms of release profile and diffusion was the main

mechanism involved in theophylline delivery.19

Vueba ML et al., studied of different ketoprofen: excipients formulations,

in order to determine the effect of the polymer substitution and type of

diluents on the drug-release mechanism. The analysis of the release profiles

in the light of distinct kinetic models led to the conclusion that the type of

polymer did not influence the release mechanism of the drug. Moreover, the

drug-release process was found to be slightly influenced by the type of

diluents.20

Harris SM et al. , developed a once-daily sustained release matrix tablet of

ibuprofen using HPMC by directly compression. Different dissolution

models were applied to drug release data in order to evaluate release

mechanisms and kinetics. The drug release data fit well to the Higuchi

expression. Drug release mechanism was found as a complex mixture of

diffusion, swelling and erosion.21

Jagan Mohan S et al., formulated controlled release matrix tablets

containing 200 mg of levodopa (LD) and 50 mg of carbidopa (CD). The

tablets were prepared by direct compression. From the in-vitro release

studies of the prepared formulations, one formula was optimized from each

polymer. HPMC K15M and CP 974P based tablet formulations showed

high release retarding efficiency. Matrix tablets produced with CP 974P

showed sticking and weight variation problems. All the formulations showed

linear release profiles (r =0.96) and sustained the release of levodopa and

carbidopa over 8–12hrs.22

6.3 OBJECTIVE OF STUDY:

The main purpose of this research is to formulate sustained release tablets of

anti-retroviral drug.

It shows sustained release action for required period of time.

It shows sustained release kinetics.

Keeping above facts in view the present work is aimed at

Preparing Sustained release tablets of antiretroviral drug using different

hydrophilic and hydrophobic polymers.

To observe the effect of various factors like polymer type, %

concentration of polymer and processing parameters on release profile

and other physical parameters of tablets.

MATERIALS AND METHOD: -

7.1 MATERIALS –

Drug : Antiretroviral drug Zidovudine.

Polymers: HPMC K15M , HPMC K4M ,HPMC K100M ,

HPMC K100LVP , HPMC E5, Kollidon SR, Carbopol 934,

Ethyl cellulose, Guar gum, Xanthan gum etc.

Lubricants : Magnesium stearate, Talc etc. :

Diluents: Micro crystalline cellulose, Lactose etc.

Glidant: Aerosil, etc.

7.2 METHODS :-

Methods of preparation: By any one of the following methods:-

By direct compression

By dry granulation

By wet granulation

Laboratory based experiments and evaluation.

Drug excipients compatibility by FTIR spectroscopy.

Estimation can be carried out by UV Spectroscopy or HPLC.

Method of collection of data :

1 Preformulation parameters:

a. Angle of repose

b. Bulk density and Tap density

c. Carr’s compressibility index

d. Hausner’s Ratio

2 Post formulation parameters:

a. Thickness

b. Weight variation

c. Hardness

7

d. Friability

e. Content uniformity

f. In vitro drug dissolution studies

g. The dissolution samples will be estimated by UV spectroscopy or

HPLC.

7.3 Source of Data:

1. Review of literature from

a) Books such as:

o Tripathi KD. Essential of medical pharmacology. 5th Ed. New Delhi.

Jypee brother; 2004.

o Goodman and Gilman’s pharmacological basis of therapeutic .USA:

McGraw- Hill;2001.1007

o Chein.TW. Novel drug delivery system, 2nd and revised ed., Marcel

Dekker Inc. New York.

o Raymond C Rowe, Paul J sheskey and Sian C Oven. Hand book of

pharmaceutical excipients; 5th Ed.

b) Journals such as:

o Indian Journal of Pharmaceutical Science

o World Journal of Pharmacy and Pharmaceutical Sciences.

o International Journal of Pharmaceutical sciences.

o Journal of Pharmacy research.

o International Journal of current pharmaceutical research.

o International Journal of Drug research Technology.

o World Journal of pharmaceutical research Formulation and

Evaluation.

o International Journal of Pharmaceutical technology research.

o International Journal of pharmaceutical and biological archives.

c) Internet Browsing:

o www.google.com

o www.ijpba.info

o Drugs.com

o Wikipedia.org

d) CD-ROM Search

7.4 Does the study require any investigation or intervention on patients or

other humans or animals? If so, please mention briefly

- Not applicable.

7.5 Has ethical clearance been obtained from your institution in case of 7.3?

- Not applicable

LIST OF REFERENCES:

1. Ratanparkhi M P, Gupta Jyoti P. Sustained release oral drug delivery

system: An overview. Int J Pharma Res & Review MAR-2013; 2(3):11-

21.

2. Isha C, Nimrata S, Rana A C, Surbhi G. Oral sustained release drug

delivery system: An overview. Int Res J Pharm 2012; 3(5):57-62.

3. Vinay Kumar, Prajapati S K, Girish C Soni, Mahendra S, Neerajkumar.

Sustained release matrix type drug delivery system: A review. World J

Pharm & Pharma Sci, ISSN 2278-4357; 1(3):934-960.

4. Sarika P, Ashutosh B, Deepak S. Sustained release matrix technology

and recent advance in matrix drug delivery system: A review. Int J Drug

Res. Tech 2013;3(1):12-20.

8

5. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World

Health Organization (WHO). AIDS Epidemic update 2007. Geneva,

Switzerland: UNAIDS. Available at http://www.unaids.org/epi/2007

6. Introduction to global AIDS: Excerpted from A Guide to Acting on

AIDS: Understanding the Global AIDS Pandemic and Responding

through Faith in Action.

7. Annabel Kanabus & Sarah Allen. The origin of AIDS and HIV and the

first cases of AIDS. [Last updated October 26,2009] Available from

http://www.avert.com

8. Provophys. Whithknight, Ri R, Jcran, Scout, Jtervorth., Human

Physilogy: Wikibook contributors 2006-2007:97-8.

9. Okimoto K, Tokunaga Y, Ibuki R, Irie T, Uekama K, Rajewski RA,

Stella VJ. Applicability of (SBE)7m–β-CD in controlled-porosity osmotic

pump tablets (OPTs). Int J Pharm 2004; 286(1-2):81-8.

10. Himansu Bhusan S, Sreenivas S A, Suddhasattya D, Himanshu S.

Formulation and evaluation of sustained release matrix tablet of a model

anti retroviral drug, Int J Pharm Sci 2011; 3(2):32-41.

11. Atul K, Ashok KT, Narendra KJ, Subheet J. Formulation and In vitro, In

vivo Evaluation of Extended Release Matrix Tablet of a Model ARV

Drug: Influence of Combination of Hydrophilic and Hydrophobic Matrix

Formers. AAPS Pharm Sci Tech 2006; 7(1) Article 1.

12. Patel Sunilkumar A, Patel Jitendra L. Design and in vitro evaluation of

novel NSAID sustained release matrix tablets based on combination of

hydrophilic and hydrophobic matrix system. World Journal of

Pharmaceutical Research Formulation and Evaluation, 1(5), 1330-1341.

13. Kannan S, Manivannan R, Ganesan K, Nishad KP, Senthilkumar N.

Formulation and evaluation of sustained release tablets of a model

NSAID drug using hydrophilic matrix system. Int. J. Pharm Tech

Res.2010; 2(3):1775-1780.

14. Basak SC, Jayakumar Reddy BM, Lucas Mani KP. Formulation and

release behavior of sustained release model drug HPMC matrix tablet.

Indian J. of Pharma Sci 2006; 68(5):594-98.

15. Deepika V, Sasikanth K. Formulation and invitro release study of a

model ARV drug sustained release tablets. Int. J. Pharma and Biological

Archives 2011; 2(3):906-13.

16. Abdul Hadi M, Srinivasa Rao A, Srinivas M, Srisha Y, Upadya

Chandrika P. Development of a floating multiple unit controlled release

beads of model drug for the treatment of AIDS. Journal of pharmacy

research 2013; 6:78-83.

17. Kar RK, Mohapatra S, Barik BB. Design and characterization of

controlled release matrix tablets of Zidovudine. Asi J Pharm and Clin Res

2009 April- June; 2(2):54-61.

18. Punna RR, Sindhura G, and Ranendra NS. Design and Study of

Lamivudine Oral Controlled Release Tablets. AAPS Pharm Sci Tech

2007; 8(4):E1- E9.

19. Evelyn O, Edna MM, Telma MK, Maria VRV, Vladi OC. Influence of

cellulose polymers type on in vitro controlled release tablets containing

theophylline. Brazilian J Pharm Sci 2007; 43(4):72-8.

20. Vueba ML, Batista de Carvalho LAE, Veiga F, Sousa JJ, Pina ME.

Influence of cellulose ether polymers on ketoprofen release from

hydrophilic matrix tablets. Eur J Pharm and Biopharm 2004; 58:51–9.

21. Harrish SM, Tazeen J, Hamid AM, Yousuf RI. Evaluation of drug

release kinetics from ibuprofen matrix tablets using HPMC. Pak J Pharm

Sci 2006; 19(2):119-24.

22. Jagan Mohan S, Kishan V, Madhusudan Rao Y, Chalapathi Rao NV.

Formulation of Controlled Release Levodopa and Carbidopa Matrix

Tablets: Influence of Some Hydrophilic Polymers on the Release Rate

and In Vitro Evaluation. Current Trends in Biotechnology and Pharmacy

2009 April; 3(2):204-9.

9 SIGNATURE OF THE CANDIDATE

(PATEL VAIDEHI HASHITKUMAR)

10 REMARKS OF THE GUIDE RECOMMENDED FOR DISSERTATION WORK.

11 NAME AND DESIGNATION OF

11.1 GUIDE

SIGNATURE

Dr. C.S.R. LAKSHMIPROFESSOR AND HEAD DEPT. OF PHARMACEUTICSNARGUND COLLEGE OF PHARMACY,

11.2 CO GUIDE

SIGNATURE

11.3 HEAD OF THE DEPT

SIGNATURE

Dr. C.S.R. LAKSHMIPROFESSOR AND HEAD DEPT. OF PHARMACEUTICSNARGUND COLLEGE OF PHARMACY,

12 REMARKS OF THE PRINCIPAL

SIGNATURE

FORWARDED AND RECOMMENDED FOR FAVORABLE CONSIDERATION.

(DR. L V G NARGUND)