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FORMULATION AND IN VITRO EVALUATION OF MATRIX TABLETS CONTAINING REPAGLINIDE. Synopsis for M.Pharm dissertation Submitted to Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka BY Mr. J. VENKATESH Dept. of Pharmaceutics BLDEA’s College of Pharmacy, BLDE University campus, Bijapur-586 103 Formulation and in vitro Evaluation of Matrix Tablets Containing Repaglinide Drug . M.Pharm Dissertation Protocol Submitted To Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore. By Mr.J.Venkatesh B.Pharm Under the guidance of Dr. C.C. Patil M.Pharm., Ph.D. Professor and Head Department of Pharmaceutics B.L.D.E.A’s College of Pharmacy, Bijapur-586103. 2012-2013. 2 Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the Candidate and Address (In block letters) Mr. J.VENKATESH, PERMANENT ADDRESS : 5#17 REPELLAWADA (V), ENKOOR (M), KHAMMAM ( DIST ), ANDHRA PRADESH - 507168 . . 2. Name of the Institution B.L.D.E A’s COLLEGE OF PHARMACY, SOLAPUR ROAD , UNIVERSITY CAMPUS, BIJAPUR , KARANATAKA – 586 103. 3. Course of study and subject M.Pharm in Pharmaceutics 4. Date of admission to Course 15-06-2011. 5. Title of the Topic Formulation and In-Vitro Evaluation of Matrix Tablets Containing Repaglinide 6. 7. Brief resume of the intended work : 6.1 Need for the study Enclosure-I 6.2 Review of literature Enclosure-II 6.3 Objectives of the study Enclosure-III Material and Methods : 7.1 Source of data : Enclosure-IV 7.2 Method of collection of data (including sampling procedure, if any) : Enclosure-IV 7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly. : Enclosure-V 3 7.4 Has ethical clearance been obtained from your institution in case of 7.3 : No 8. List of References (about 4-6) 9. Signature of candidate 10. Remarks of the guide 11. Name & Designation of (in block letters) 12. 11.1 Guide 11.2 Signature 11.3 Co-Guide (if any) 11.4 Signature 11.5 Head of Department 11.6 Signature : Enclosure-VI : Enclosure-VII Dr. C.C .PATIL Professor & Head Department of Pharmaceutics B.L.D.E.A’s College of Pharmacy, BIJAPUR-586 103 Dr. C. C. PATIL Professor & Head Department of Pharmaceutics B.L.D.E.A’s College of Pharmacy, BIJAPUR-586 103 12.1 Remarks of the chairman & principal: This study can be carried out in our laboratory 12.2 Signature 4 ENCLOSURE-I 6) Brief resume of the intended work: 6.1. Need for the study: Among various dosage forms, matrix tablets are widely accepted for oral sustained release (SR) as they are simple and easy to formulate. Matrix system is the release system, which prolongs and controls the release of drug that is dissolved or dispersed. Sustained release formulations are preferred for such therapy because they maintain uniform drug levels, reduce dose and side effects, better patient compliance, and increase safety margin for high potency drugs. Oral administration of drugs has been the most common and preferred route for delivery of most therapeutic agents. It remains the preferred route of administration investigated in the discovery and development of new drug candidates and formulations.1 Repaglinide is an oral blood glucose-lowering drug of the meglitinide class used in the diabetis mellitus. Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and it diminishes at low glucose concentrations.The mean absolute bioavailability is 56%.2,10 It has a short plasma half-life of 2 to 4 hours, but this drug is likely to be absorbed or degraded in the stomach and small intestine Therefore it is preferred to use in the matrix dosage form. 5 ENCLOSURE-II 6.2. Review of literature Praveen S. Hiremath et al., have developed controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24 h for both the drugs despite of the wide variations in their physicochemical properties.3 Anna Viriden et al., have developed the release of a model drug substance, methylparaben, was studied in matrix tablets composed of hydroxypropyl methylcellulose (HPMC) batches of the USP 2208 grade that had different chemical compositions. It was found that chemically heterogeneousHPMCbatches with longer sections of low substituted regions and lower hydroxypropoxy content facilitated the formation of reversible gel structures at a temperature as low as 37 ◦C. Most importantly, these structures were shown to affect the release of the drug from matrix tablets, where the drug release decreased with increased heterogeneity and a difference in T80 values of 7 h was observed between the compositions. This could be explained by the much lower erosion rate of the heterogeneous HPMC batches, which decreased the drug release rate and also released the drug with a more diffusion based release mechanism compared to the less heterogeneous batches. It can therefore be concluded that 6 the drug release from matrix tablets is very sensitive to variations in the chemical heterogeneity of HPMC.4 Mina Ibrahim Tadros has developed a gastroretentive controlledrelease of drug delivery system with swelling, floating, and adhesive properties. Ten tablet formulations were designed using hydroxypropylmethylcellulose (HPMC K15M) and/or sodium alginate (Na alginate) as release-retarding polymer(s) and sodium bicarbonate (NaHCO3) or calcium carbonate (CaCO3) as a gas former. Swelling ability, floating behaviour, adhesion period and drug release studies were conducted in 0.1 N HCl (pH 1.2) at 37 ± 0.5 _C. The tablets showed acceptable physicochemical properties. Drug release profiles of all formulae followed non-Fickian diffusion. Statistical analyses of data revealed that tablets containing HPMC K15M (21.42%, w/w), Na alginate (7.14%, w/w) and NaHCO3 (20%, w/w) (formula F7) or CaCO3 (20%, w/w) (formula F10) were promising systems exhibiting excellent floating properties, extended adhesion periods and sustained drug release characteristics. Both formulae were stored at 40 _C/75% RH for 3 months according to ICH guidelines. Formula F10 showed better physical stability. Abdominal X-ray imaging of formula F10, loaded with barium sulfate, in six healthy volunteers revealed a mean gastric retention period of 5.50 ± 0.77 h.5 Harikrishna Boyapally et al., have developed theophylline buccal adhesive tablets using direct compression. Buccal adhesive formulations were developed using a water soluble resin with various combinations of mucoadhesive polymers. The prepared theophylline tablets were evaluated for tensile strength, swelling capacity and ex vivo mucoadhesion performance. Ex vivo mucoadhesion was assessed using porcine gingival tissue and the peak detachment forces were found to be suitable for a buccal adhesive tablet with a maximum of 1.5N approximately. The effect of formulation composition on the release pattern was also investigated. Most formulations showed theophylline controlled release profiles depended on the grade and polymer ratio. The release mechanisms were found to fit Peppas’ kinetic model over a period of 5 h. In general the majority of the developed formulations presented suitable adhesion and controlled drug release.6 J.C.O. Villanova et al., have developed design of new excipients that extend the release of drugs from tablets over prolonged periods is essential in reaching enhanced therapeutic performances. In this sense, the objective of this study was to develop new excipients, based 7 on acrylic monomers (ethyl acrylate, methyl methacrylate, and butyl methacrylate) for use in direct compression (DC). The polymeric excipients were prepared by suspension and emulsion polymerization reactions and were characterized by FTIR to confirm the polymerization reaction. For the success of direct compression, excipients must present good flow and compactability properties. Therefore, excipients were submitted to analysis of morphology (SEM), particle size and size distribution by laser diffraction, and powder density (bulk density and tapped density). The Carr index, Hausner ratio, flow ratio, and cotangent of the angle a were determined. Thereafter, the polymeric excipients were used to prepare inert matrices by DC using propranolol hydrochloride (PHCl) as a model drug. The tablets were evaluated for average weight, breaking force, and friability tests. The release profiles were determined, and the dissolution kinetics was studied. The results indicated that matrices prepared from excipients obtained by suspension polymerization (NWCB and PECB) presented a release of PHCl for a period exceeding 12 h, most likely due to the higher micromeritic properties. The results suggested that the increase in the percentage of polymers, as well as in the compression time, resulted in a higher hardness of the matrix with a reduced rate release of the PHCl. Finally, in vitro preliminary tests showed that the polymeric excipients produced were non-toxic for the gingival fibroblasts.7 M.A. Holgado et al., have developed a new pharmaceutical formulation for the administration of morphine. This system is based on a polymeric complex previously characterized. After the studies performed, it has been selected the following formulation: 62.5% of morphine complex, 15% of free morphine and 22.5% of Eudragit_ RS. The morphine formulation proposed has been characterized by means of the study of the influence of several parameters such as pH, ionic strength, mean particle diameter of the components and total morphine dose by means of the tablet dimensions. This assayed formulation is able to provide a specific in vitro release profile that will be no influenced by possible variations in the GIT conditions. Moreover, this formulation can reproduce the same biopharmaceutical behaviour in an independent manner of the mean diameter particle of the components and the dimension of the tablet produced with several doses inside a wide interval of doses.8 Matej Pavli et al., have developed matrix tablet by using polymeric polyelectrolytes as matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan (CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM) were investigated according to their water-uptake/erosion properties, in situ complexation 8 ability of CARR with DM, and the possibility to achieve dual drug release control. Interactions between different CARR types (_-, _-, and _-) and DM were confirmed by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta potential measurements. Combination of water-uptake/erosion with in situ complexation prolonged DM release from CARR matrices for more than 24 h. The rate order of drug release was in accordance with the number of ester sulfate moieties per disaccharide unit of CARRs (_ (1) > _ (2) >_ (3)). The higher the charge on the CARR backbone, the higher the number of interactions with DM and the slower the drug release. Low pH, more vigorous hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta potential measurements of DM and CARRs, proposed influence of counterion condensation and its effect on screening polyelectrolyte–drug interactions was confirmed to lower in situ DM–CARR complexation. Dual drug release control from polyelectrolyte matrices by wateruptake/erosion and in situ complexation offers many new approaches for designing controlled-release systems.9 ENCLOSURE-III 6.3. Objectives of the study : The present work is planned with the following objectives. 1. To prepare matrix tablets by wet granulation technique using hydrophilic polymers such as methyl cellulose, hydroxypropylmethylcellulose , hydroxyethyl cellulose and sodium carboxy methyl cellulose. 2. To examine the granules for angle of repose, compressibility index, bulk density etc. 3. To evaluate the tablets for hardness, weight variation, uniformity in drug content, drug-polymer interactions, nature of drug in the formulations and surface morphology. 4. To study the in vitro drug release from the prepared tablets. 5. To carry out the stability studies on the prepared formulations. 9 ENCLOSURE-IV 7) MATERIALS AND METHODS : 7.1. Source of data The data will be collected by performing various laboratory experiments, referring journals, text books and other literature. 7.2. Method of collection of data: The whole data is planned to collect from laboratory experiments which includes the following, 1) The matrix tablets of Repaglinide will be prepared using the hydrophilic polymers such as methyl cellulose, hydroxypropylmethylcellulose , hydroxyethyl cellulose and sodium carboxy methyl cellulose etc. 2) The granules will be evaluated for angle of repose, compressibility index and bulk density. 3) The formulations will be characterized by Differential scanning calorimetry (DSC), Infrared Spectroscopy (FTIR), x-ray Diffraction Studies (XRD), Scanning Electron Microscopy (SEM) and data will be collected. 4) The effects of formulation variables on the drug release will be studied by conducting dissolution experiments . 5) The stability studies of the formulations will be carried out as per ICH guidelines and data will be collected. 10 ENCLOSURE-V 7.3 The in vivo studies in the animals will not be carried out in the laboratory . ENCLOSURE-VI 8) List of references: 1) Nilesh V. 2011 “Ingle Preparation and Evaluation of Ambroxol hydrochloride matrix tablet using different Combination of Polymers” ,31 309-313. 2) UK Drug Information Pharmacists Group May 1999 4/99/06. 3) Praveen S. Hiremath, Ranendra N. Saha 2008 “Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: Design and in vitro evaluations” Int. J. of Pharm. 362 118–125. 4) Anna Viriden Anette Larssona, Herje Schagerlöfb, Bengt Wittgrenc 29 September 2010 “Model drug release from matrix tablets composed of HPMC with different substituent heterogeneity”, Inter J of Pharma 401 60–67. 5) Mina Ibrahim Tadros November 2009, “Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride”, European Journal of Pharm and Biopharmaceutics 74 - 332–339. 6)J.C.O. Villanova a,, E. Ayres b, R.L. Oréfice, July 2011 “Design of prolonged release tablets using new solid acrylic excipients for direct compression”, European Journal of Pharmaceutics and Biopharmaceutics 79 - 664–673 29 . 7) M.A. Holgado A. Iruin, J. Alvarez-Fuentes, M Fernández-Arévalo June 2008 “Development and in vitro evaluation of a controlled release formulation to produce wide dose interval morphine tablets”, European Journal of Pharmaceutics and Biopharmaceutics 70 544–549 6 . 8) Matej Pavli Franc Vreˇcer, Saˇsa Baumgartner August 2010 “Matrix tablets based on carrageenans with dual controlled release of doxazosin mesylate”, International Journal of Pharmaceutics 400 15–23. 9) Krishna Reddy K.V.S.R., MosesBabu J., Mathad V.T., Eswaraiah, S., Reddy S. M., Dubey P.K. and Vyas K.,2003 “Impurity Profile Study of Repaglinide”, J.Pharm.Biomed. Anal.,32, , 461-467. 10) Guay DRP 1998. Repaglinide, a novel, short-acting hypoglycaemic agent for Type 2 diabetes mellitus. Pharmacotherapy; 18: 1195-204 11 ENCLOSURE-VII 9) Remarks of the Guide: The present work is aimed to formulate the matrix tablets for anti diabetic drug, Repaglinide. It is a metaglinide derivative which is used to treat type II diabetes mellitus. It is particularly useful for patients who require control of post-prandial glucose levels.When administered orally, 50% of bio availability is obtained with a half life of 1hr.It is short acting with rapid onset of action. It has a short plasma half-life of 2 to 4 hours, but this drug is likely to be absorbed or degraded in the stomach and small intestine Therefore it is preferred to use in the matrix dosage form. The proposed study can be carried out in the laboratory. Dr. C .C. PATIL Professor and HOD 12