FORMULATION AND EVALUATION OF CONTROLLED-POROSITY OSMOTIC PUMP TABLETS OF ZIDOVUDINE
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560041
By
Mr. BOBADE VITTHAL SHIVAJI.B. Pharm.
Under the Guidance
of
Dr. A .M. GODBOLE.M Pharm Ph D.
Department of Pharmaceutics
S.E.T’s COLLEGE OF PHARMACY
S. R. Nagar, Dharwad–580002
2012-2013
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS / Mr. BOBADE VITTHAL SHIVAJIDEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY,
S.R.NAGAR,
DHARWAD-580002
2. / NAME OF THE INSTITUTION / SET’s COLLEGE OF PHARMACY,
S. R. NAGAR,
DHARWAD-580002
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION TO COURSE / 23/06/2012
5. / TITLE OF THE TOPIC
FORMULATION AND EVALUATION OF CONTROLLED-POROSITY OSMOTIC PUMP TABLETS OF ZIDOVUDINE
6.
7.
8. / BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
Oral drug delivery system has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms.1 Conventional oral drug administration does not usually provide rate-controlled release or target specificity. In many cases, conventional drug delivery provides sharp increase in the drug concentration at potentially toxic levels. Following a relatively short period at the therapeutic level, drug concentration eventually drops off until re-administration2. However significant stride has been made in the development of drug delivery devices that can precisely control the rate of drug release for an extended period of time. In the recent years, pharmaceutical research has led to the development of several novel controlled drug delivery systems of which oral controlled drug delivery system has received greater attention since it is most popular route of drug administration.3
Many controlled drug delivery devices like microspheres, liposomes, nanoparticles etc have been produced to deliver the active medicament with a predetermined and predictable rate in a reproducible manner for prolonged period of time by various routes of administration like buccal, nasal, ocular, vaginal routes of administration.
Among these, osmotic pump tablet for oral administration offers several advantages, such as ease of administration,reducing risk of adverse reactions and improved patient compliance.
Osmotic drug delivery systems utilize osmotic pressure as energy source and driving force for delivery of drugs. pH, presence of food and other physiological factors may affect drug release from conventional Controlled Release systems (matrices and reservoirs), whereas drug release from per oral osmotic systems isindependent of these factors to a large extent . Many different systems have been developed based on principles of osmotic pressure such as elementary osmotic pump (EOP), sandwiched osmotic tablet system (SOTS), push–pull systems, controlled porosity osmotic pumps, asymmetric membrane osmotic pumps, single composition osmotic tablet(SCOT)and osmotic systems made by swellable core technology.4
Osmotic pump tablet has advantages, such as (1) releasing drug at anapproximately constant rate up to 24 hr; (2) Releasing drug independent of environment media; (3) Exhibiting comparable in vitro/ in vivo drug release.5
Zidovudine, the first antiHIV drug approved for clinical use and is widely used for treatment ofAIDS either alone or in combination with other antiviralagents. However, the main limitation to therapeutic effectiveness of zidovidine is its dose-dependent hematological toxicity, short biological half-life, and poor bioavailability.6
Treatment of AIDS using conventional formulations of zidovidine is found to have many drawbacks such as adverse side effects due to accumulation of drug in multi-dosetherapy. Poor patient compliance6 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.7
In the proposed work the porosity osmotic pump tablets of zidovudine will be formulated to achieve controlled release to overcome the inherent drawbacks of conventional dosage forms, to achieve steady state plasma concentration and to increase the therapeutic efficacy of zidovudine.
6.2 REVIEW OF LITERATURE:
Polymeric microspheres for controlled drug release have been formulated. The controlled release of medications from polymer microspheres is achievable by manipulating the physical and chemical properties of the polymer as well as those of the microspheres. Issues such as polymer molecular weight, blend composition, polymer and drug crystallinity, drug distribution, sphere porosity, and sphere size all influence the release profile and can be tailored to fit a desired release.2
The extended release controlled porosity osmotic pump formulation of model drug Glipizide were developed using a wicking agent. The effect of different variables like level of wicking agent solubilizing agent, level of pore former and membrane weight gain on in vitro release were studied. They found that drug release is affected by level of wicking agent and solubilizing agent in the core. Glipizide release from controlled porosity osmotic pump was directly proportion to the pore former(sorbital) and inversely proportion to membrane weight gain.3
A new type of elementary osmotic pump (EOP) tablet for efficient delivery of poorly water-soluble/practically insoluble drugs was designed. Drug release from the system, called swellable elementary osmotic pump (SEOP), is through a delivery orifice in the form of a very fine dispersion ready for dissolution and absorption. The SEOP was simple to prepare, because there was no need for a push compartment. The results showed that the SEOP can be a very effective device for the delivery of poorly water-soluble drug with zero order pattern. These devices can release their drug contents in a form of soluble or solid suspended particles out of the system by constant release rate. The main system characteristics including D24h, tL,RSQzeroand D%zero can be improved by optimizing the formulation parameters. The optimized system inthis study was able to release indomethacin at a zero order kinetics for 24 h when tested at pH 6.8 medium.4
Bilayer-core osmotic pump tablet were prepared by coating the indented core tablet. The bilayer-core consisted of two layers: (a) push layer and (b) drug layer, and was made with a modified upper tablet punch, which produced an indentation at the centre of the drug layer surface. Such a bilayer-core osmotic pump tablet was able to deliver nifedipine at an approximately constant rate up to 24 h, independent on both release media and agitation rate. Since the drug layer identification and laser drilling could be eliminated by employing this strategy.5
Controlled-porosity osmotic pump tablet utilizing (SBE)7m-β-CD which serves as both a solubility modulator and as an osmotic pumping agent for osmotic pump tablets,from which the release rate of both water-soluble and poorly water-soluble drugs can be controlled were formulated. For soluble drugs (SBE) 7m-β-CD acts primarily as an osmotic and an osmotic pump tablet control agent. Significantly, (SBE) 7m-β-CD not only enhances the delivery of poorly soluble drugs from osmotic pump tablets but acts a controlling excipient for soluble drugs such that the release rate, corrected for table surface area, of both poorly soluble and soluble drugs are similar.7
A controlled porosity osmotic pump tablets for salvianolic acid were prepared and optimized with an experimental design methods including an artificial neutral network method. Three casual factors, i.e., drug, osmotic pressure promoting agent rate, PEG 400 content in coating solution and coating weight, were evaluated based on their effects on drug release rate. The linear correlation coefficient of the accumulative amount of drug release and time of 12h, r (Y1), and the sum of the absolute value between measured and projected value, Y2, were used as outputs to optimize the formulation. The release rate of salvianolic acid was found to be inversely proportional to the concentration of the plasticizer. The salvianolic acid release rate increased as the pore forming substance in the coated membrane increased. The salvianolic acid release rate from microporous membrane was affected by and is inversely proportional to overall coating weight.8
A microbial triggered colon-targeted osmotic pump has been studied. The gelable property at acid condition and colon specific biodegradation of chitosan were used to: (1) produce the osmotic pressure (2) from the drug suspension and (3) from the in situ delivery pores for colon specific drug release, respectively. The effect of formulation variables, including the level of pH-regulating excipient (citric acid) and the amount of chitosan in the core, the weight gain of semipermeable membrane and enteric-coating membrane, and the level of pore former (chitosan) in the semipermeable membrane have been studied. Results of SEM showed that the in situ delivery pores could be formed in predeterminated time after coming in to contact with dissolution medium and the number of pore was dependent on the initial level of pore former in the membrane. The effects of variations in the level of citric acid and chitosan in the core formulation on drug release were studied. Drug release was directly proportional to the initial level of pore former, but inversely related to the membrane weight the amount of chitosan in core formulation had a profound effect on the amount of the drug release.9
Thenumber of marketed oral osmotically driven systems (OODS) has doubled in the last 10 years. Themain clinical benefits of OODS are their ability to improve treatment tolerability and patient compliance.These advantages are mainly driven by the capacity to deliver drugs in a sustained manner, independentof the drug chemical properties, the patient’s physiological factors or concomitant food intake. In this study they have given an overview of the OODS development in the last30 years, detailing the technologies, specific products and their clinical use. Overall, oral osmotically drivensystems appear to be a promising technology for product life-cycle strategies.10
Theporous osmotic pump tablets were designed by using osmotic agent sodium chloride and pore former PEG 400 and they were considered as independent variables. The increase in concentration of pore former and osmotic agent after a limit, changes therelease from zero order to Higuchi based release. They observed
independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of theoptimization procedure in successful development of porous osmotic pump tablets containing diclofenac sodium by using sodium chloride and PEG400 as key excipients. Stability studies revealed that optimized formulation is stable.11
A method for the preparation of monolithic osmotic pump tablet was obtained by coating the indented core tablet compressed by the punch with a needle. Atenolol was used as the model drug, sodium chloride as osmotic agent and polyethylene oxide as suspending agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer for controlling membrane permeability. The Prepared osmotic tablet is simplified by coating the core tablet with indentation and the cost is reduced with the elimination of laser drilling. This method may be promising in the field of the preparation of osmotic pump tablet.12
6.3OBJECTIVE OF STUDY:
The objectives of the proposed study are:-
Preparation of standard calibration curve of zidovudine
To carryout compatibility studies between drug and polymer.
To formulate osmotic tablets containing zidovudine
by a suitable method.
To evaluate formulations for various quality control parameters.
Materials and methods:
materials:
Drug:zidovudine
Semipermeable membrane: like cellulose acetate, ethyl cellulose etc.
Pore forming agents: like PEG 400, Sorbitol, etc.
7.1 METHOD :
- Preparation of tablet core: The active agent and excipients will be formulated into tablet by suitable granulation technique using different polymers with different ratios along with other regular excipients.
B.EVALUATION STUDIES :
Pre compression studies :
Bulk density.
Tapped density.
Carr’s index.
Angle of repose.
Porosity.
Post compression studies :
Thickness.
Hardness.
Friability.
Weight variation.
Content uniformity
SEM (Scanning Electron Microscopy).
DSC( Differential Scanning Calorimetry)
FT-IR
In vitro Dissolution studies
7.2SOURCE OF DATA :
- Text books
- care.com
- online.com
CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? IF SO
PLEASE MENTION BRIEFLY.
No.
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTION IN CASE OF 7.3?
Not applicable.
LIST OF REFERENCES:
1.Chien YW. Novel Drug Delivery Systems. 2nd ed. New York:Informa Healthcare; 2009.p.139.
2.Freiberg S, Zhu XX. Polymer microspheres for controlled drug release. Int J Pharm 2004;282:1-18.
3.Mahalaxmi R, Phanidhar S, Ravikumar, Atin K, Pritam KD, Narkhede R. Enhancement of dissolution of glipizide from controlled porosity osmotic pump using a wicking agent and a solubilizing agent. Int J Pharm Sci Res 2009 July-Sept;1(3):705-11.
4.Shokri J, Ahmadi P, Rashidi P, Shahsavari M, Siahboomi AR, Nokhodchi A. Swellable elementary osmotic pump (SEOP): An effective device for delivery of poorly water-soluble drugs. Eur J Pharm Biopharm 2008;68:289-97.
5.Liu L, Xu X. Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet. Int J Pharm 2008;352:225-30.
6.Provophys. Whithknight, RiR, Jcran, Scout, Jtervorth., Human Physilogy: Wikibook contributors 2006-2007.p.97-8.
7.Okimoto K, Tokunaga Y, Ibuki R, Irie T, Uekama K, Roger A, et al. Applicability of (SBE)7m–β-CD in controlled-porosity osmotic pump tablets (OPTs). Int J Pharm 2004;286:81-8.
8.Wen-Jin X, Ning L, Chong-kai G. Preparation of controlled porosity osmotic pump tablets for salvianolic acid and optimization of the formulation using an artificial neural network method. Acta Pharm Sinica B 2011;1(1):64-70.
9.Hui L, Xing-Gang Y, Shu-Fang N, Lan-Lan W, Li-Li Z, Hong L, et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation. Int J pharm 2007;332:115-24.
10.Malaterre V, Ogorka J, Loggia N, Gurny R. Oral osmotically driven systems:30 years of development and clinical use. Eur J Pharm Biopharm 2009;73:311-23.
11.Edavalath S, Shivanad K, Kalyani P, Rao BP, Divakar G. Formulation development and optimization of controlled porosity osmotic pump tablets of Diclofenac sodium. Int J Pharm Pharm Sci 2011;3(1):80-7.
12.Lui L, Che B. Preparation of monolithic osmotic pump system by coating the intended core tablet. Eur J Pharm Biopharm 2006;64:180-4.
13.Kieburtz KD, Seidllin M, Lambert JS, Dollis R, Reichman R, Valentine T. Extended follow-up of neuropathy in patients with AIDS and AIDS related complex treated with dideoxyinosine. J Acquir Immuno Defic Syndrom.1992;5:60Y64.
14. Re MC, Bon I, Monari P, Gorini R, Schiavone P,Gibellini D, et al.Drug failure during HIV-1 treatment. New perspectives in monitoring drug resistance. New Microbiol 2003;26 (4): 405-13.
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9. / SIGNATURE OF CANDIDATE10. / REMARK OF THE GUIDE
The above information and literature has been extensively investigated, verified and was found to be correct. The present study will be carried out under my supervision and guidance.
11. / 11.1 NAME AND DESIGNATION
OF THE GUIDE
11.2 SIGNATURE / Dr. A .M. GODBOLE M Pharm Ph D.
PROFESSOR
DEPT.OF PHARMACEUTICS,
S E T’sCOLLEGE OF PHARMACY,
S. R. NAGAR, DHARWAD-580002.
11.3 NAME AND DESIGNATION
OF CO-GUIDE
11.4 SIGNATURE / ------
11.5 HEAD OF THE
DEPARTMENT
11.6 SIGNATURE / Prof. S. P. THAKKER M. Pharm.
PROFESSOR AND HEAD,
DEPT.OF PHARMACEUTICS,
S E T’sCOLLEGE OF PHARMACY,
S. R. NAGAR, DHARWAD-580002.
12. / 12.1 REMARK OF THE
PRINCIPAL / The above mentioned information is correct and I recommend the same for approval.
12.2 SIGNATURE / Dr. V. H. KULKARNI M.Pharm, Ph.D.,
PROFESSOR AND PRINCIPAL,
S E T’s COLLEGE OF PHARMACY
S. R. NAGAR,
DHARWAD-580002.
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