“formulation and evaluation of sustained...
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“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)