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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,KARNATAKA. ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1 Name of the candidate and address K. NAVEEN PERMANENT ADDRESS S/O K.SUNDARA RAJA GUPTA BAZAR STREET, BHAKARAPET (P.O), CHITTOOR(D.T), ANDHRA PRADESH. 2 Name of the institution KRUPANIDHI COLLEGEOF PHARMACY, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore – 560035 3 Course of study and subject MASTER OF PHARMACY IN PHARMACEUTICS 4 Date of the admission JUNE 2009 5 Title of the topic: “DEVELOPMENT AND EVALUATION OF VOGLIBOSE TABLETS ” 1 6. Brief resume of the intended work: 6.1 Need for the study: Presently, there are about 150 million diabetic patients worldwide, out of which 33 million are in India alone. As per WHO estimates, the number of diabetics worldwide would increase to 300 million by 2025, with India will become the Diabetes capital of the world.1 The delivery of drugs for management of Diabetes in solid oral dosage forms is desirable from both economic and compliance point of view. These drugs have the capacity to improve the quality of patient life substantially. α- glucosidase inhibitors are oral anti-diabetic drugs. These drugs are competitive inhibitors of the intestinal α- glucosidases and reduce post meal excursions by delaying digestion and absorption of starch and disaccharides.2 Their mechanism of action being limited to the intestinal brush border membrane, and owing to their structural features, they have limited systemic bioavailability, due to which they have much reduced side-effect profile compared to contemporary antihyperglycemic drugs. A large section of people are diagnosed to be suffering from pre-diabetes condition (such as obesity) and to treat that condition alphaglucosidase inhibitors is widely prescribed. There are currently three drugs which belong to this class - acarbose, miglitol and voglibose, of which voglibose is the newest. Voglibose scores over both acarbose and miglitol in terms of lower side effects profile.3 Voglibose is 20 to 30 fold more potent competitive inhibitor of intestinal alpha-glucosidase than acarbose. Beneficial effects of voglibose have been demonstrated both in human and rodents with diabetes.4 The drug has been clinically used to improve glucose tolerance by inhibiting digestion and absorption of glucose from the intestine without promoting insulin secretion. In diabetic patients, post-prandial impaired glucose tolerance (IGT) level is observed leading to hyperglycemia. To reduce hyperglycemia and IGT, voglibose tablets can be used. These tablets release their medicaments in intestine and act locally to avoid the hyperglycemia by competitively binding with the disaccharidases in intestine and the activity will become low and through these events patient compliance is improved. The oral route is a route of choice for the patients because they are effective and self medication is possible. Solid oral dosage forms utilize relatively inexpensive technology and are compact and their appearance can be modified to create brand identification and patient compliance. They are usually available in various formulations such as tablets, 2 capsules and powders. In the preparation of tablets, based on the drug, different excipients are selected by performing various preformulation studies. It is always a challenge to develop lowcost non-patent infringing formulations for the generic market. Therefore, in the present investigation, an attempt will be made to develop a patent non-infringing generic formula of a tablet of α-glucosidase inhibitor (voglibose) and characterize the product using appropriate evaluation parameters. 6.2 Objectives of the study: The primary aim of the proposed project is to develop voglibose tablets. In order to fulfill the aim, the following objectives have to be achieved: 1. Preformulation studies for selection of suitable excipients to develop a suitable tablet based on physicochemical properties of drug and excipients. 2. Screening of excipients to check compatibility and efficacy for developing the tablets. 3. Formulation development of the Tablet dosage form 4. Study of pre-compression parameters of the formulation. 5. Evaluation of compressed products, identification and troubleshoot compression defects, if any. 6. Optimizing the product to comply with official specifications / standards. 7. Study the stability of the formulation as per ICH guidelines. 6.3 Review of the literature: Oral route is the most suitable method of administering the drugs for systemic effect. It is the preferred route for most therapeutic agents owing to its patient acceptance; convenience of administration, cost-effective manufacturing and most importantly it does not require sterile processing and generally have long shelf life. The tablets are perhaps the simplest, most common and most economical method of processing an active agent into a drug delivery product.5,6 Tablets are sufficiently resistant to shock and abrasions to withstand handling during manufacturing / packaging / transport. As the tablets are unit dosage form they together offer greatest capabilities of all oral dosage form for the greatest dose precision and least content variability. The unit cost is lowest as compared to all other dosage forms, well situated for large-scale production and easiest, cheapest to package and ship. They provide the greatest ease of swallowing with the least tendency to hang up above the stomach.6 3 The solid oral dosage forms have to be analyzed regularly for their in vitro performance as per official and un-official methods such as assay, weight and content uniformity, size, shape, color, hardness, disintegration, dissolution, etc. following pharmacopoeial or drug authority recommendations and ensuring GMP compliance at each stage of production and testing .7,8 The generic formulations should be non-patent infringing with respect to excipients, their quantities and manufacturing methodologies and hence need considerable intellectual inputs from the formulators to arrive at the best possible formulation which could be accepted by the drug authorities. Further, the formulations should comply with standards and safety specifications of the regulated market for which it is intended. In the formulation of the generic products, the formulator mainly aims to match the dissolution profile of the generic product with the innovator product by in vitro release studies or otherwise prove the bioequivalence of the product compared to the innovator brand or (Reference Listed Drug) RLD product. For suitable category of drugs there may be bio-waiver, and hence a huge savings on the part of the sponsor company.9 In addition, the growth of the pharmaceutical industry as well as increased competition from both foreign and domestic markets require that a tablet manufacturer have greater concern regarding the economics of tablet production by introducing the less laborintensive, higher productive manufacturing methods for making the increasing number of tablet products available today .10 Type 2 diabetes accounts for 90% to 95% of all known cases of diabetes. Although it normally occurs among older, inactive individuals, children and adolescents are increasingly identified, contributing to the growing pool of patients who require lifelong care. Progressive in nature, type 2 diabetes begins with peripheral insulin resistance and ends in complete loss of insulin secretion if the disease progresses through its entire natural history. Initially, pancreatic beta cells are able to compensate for insulin resistance by increasing basal and postprandial insulin secretion. In time, however, compensation fails as beta cells exhaust their capacity to react appropriately to rising glucose concentrations. A deterioration of glucose homeostasis ensues, and glucose intolerance develops. Left untreated, intolerance worsens, and the diabetic state is manifested. 11 α- Glucosidase inhibitors are being recently used for the treatment of hyperglycemia in patients with type 2 diabetes mellitus. These drugs can delay digestion of complex 4 carbohydrates by acting locally at the small intestine as competitive inhibitors of the intestinal glucosidase enzyme. It has been shown that these drugs in the presence of carbohydrate administration reduce significantly the postprandial rise in plasma insulin both in nondiabetics and in type 2 diabetic patients, an effect that is secondary to the reduced peaking in postprandial glycemic levels. This effect is thought to be desirable because it may inhibit the overwork of the pancreatic cells and may avoid hyperinsulinemic state probably related to ischemic heart disease. 12 Voglibose is a valiolamine derivative.13 Voglibose is an anti-diabetic agent and it belongs to alpha-glucosidase inhibitors class. It competitively and reversibly inhibits the alpha–glucosidase enzymes; glucoamylase, sucrose, etc and it acts by delaying the digestion and absorption of sugar. Voglibose is slowly and poorly absorbed, and is rapidly excreted. Little metabolism occurs and no metabolites have as Structure of voglibose yet been found .Voglibose should be administered in conjunction with diet treatment or diet plus a sulfonylurea. Some investigators recommend the use of voglibose only in patients who achieve satisfactory fasting glucose level.14 The predicted water solubility of voglibose is 1.90 x 102 mg/ml, calculated using ALOGPS.15 The inhibition power of voglibose on alpha-glucosidase is evaluated by performing an inhibition assay in an Enzyme-Immobilized amino-microplate.16 The determination of voglibose in pharmaceutical tablets is performed with a highly sensitive liquid chromatographic procedure with post-column derivatization using fluorescence detection (LCFD).17 5 7 Materials and methods: 7.1 Source of data: Data will be obtained from drug bank, rxlist, Pubmed, Science Direct, Medline, US patent office website and other Internet facilities, literature search, and related articles from library of Krupanidhi College of Pharmacy and Bal Pharma ltd.. 7.2 Method of collection of data (including sampling procedures if any): Data on drugs will be collected from drug information center, standard books, physicochemical database, and literature search. Extensive Preformulation trial provides the basis of selecting the excipients and system for final formulation development. The precompression studies include the particle size, adhesion and cohesion of particles, wettability, moisture content and hygroscopicity, effect of lubricants and adhesives. The post compression parameters include identification of defects in the tablets, weight variation, content uniformity, friability, Disintegration, dissolution studies. 7.3 Does the study require any investigation or interventions to be Conducted on patients or other humans or animals? No. 7.4 Has ethical clearance been obtained from your institution in case of 7.3? Not Applicable 6 8 List of References: 1. http://www.medicalnewstoday.com/articles/36827.php [Access date : 2009 Nov 27] 2. Nolte MS. Pancreatic Hormones & Antidiabetic Drugs. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and clinical pharmacology. 11th ed. New Delhi: Tata McGraw Hill Education Private Limited; 2009. p. 742-4. 3. http://en.wikipedia.org/wiki/Voglibose [Access date : 2009 Nov 27] 4. Yasuda K, Shimowada K, Uno M, Odaka H, Adachi T, Shihara N et al. Longterm therapeutic effects of voglibose, a potent intestinal alpha-glucosidase inhibitor, in spontaneous diabetic GK rats. Diabetes Res Clin Pract 2003;59(2):113-22. 5. Speers M, Bonnano C. Economic aspects of controlled drug delivery. In: Mathiowitz E, editor. Encyclopedia of controlled drug delivery. New York: Wiley Interscience; 1999. vol 1. p. 342-7. 6. Peck GE, Baley GJ, Banker SG. Tablet formulation and design. In: Lieberman HA, Lachman L, Schwartz JB editors. Pharmaceutical dosage forms: tablets. New York: Marcel Dekker Inc; 2005. p. 131-245. 7. USP-NF 18. 23rd ed. Rockville: The United States Pharmacopoeial Convention Inc; 1996. 8. http://www.who.int/medicines/areas/quality_safety/quality_assurance/gmp/en/ index.html. [Access date: 2009 Nov 27]. 9. http://www.fda.gov/ohrms/dockets/ac/00/slides/3657s2_01_hussain/ [Access date : 2009 Nov 27]. 10. Banker GS, Anderson NR. Pharmaceutical dosage forms: tablets. In: Lieberman HA, Lachman L, Kanig JL, editors. Volume 3. 2nd ed. New York: Marcel Dekker Inc; 1990. 11. Stolar MW, Chilton RJ. Type 2 diabetes, cardiovascular risk, and the link to insulin resistance. Clin Ther 2003;25 Suppl B:B4-31. 12. Hirose T, Miyashita Y, Takagi M, Sumitani S, Kouhara H, Kasayama S. Characteristics of type 2 diabetic patients responding to voglibose administration as an adjunct to sulfonylurea. Diabetes Res Clin Pract 2001 Oct;54(1):9-15. 13. Kageyama S, Nakamichi N, Sekino H, Nakano S. Comparison of the effects of acarbose and voglibose in healthy subjects. Clin Ther 1997 Jul-Aug;19(4):720-9. 14. http://www.voglibose.com/ [Access date : 2009 Nov 27] 7 15. http://www.drugbank.ca/drugs/DB04878 [Access date : 2009 Nov 27] 16. Matsui T, Shimada M, Saito N, Matsumo K. Alpha-glucosidase inhibition assay in an enzyme-immobilized amino-micro-particulate. Anal Science 2009 Apr;25(4):559-62. 17. Woo JS, Ryu JK. Quantitative determination of pharmaceutical tablets using highperformance liquid chromatography-fluorescence detection with column derivatization and mass spectrometric detection. J Pharm Biomed Anal 2006 Sep 26;42(3):328-33. 8 9. Signature of the Candidate (K. NAVEEN)((Rajesh 10. Remarks of the Guide: Product development for generic marketing is a promising field. Formulation strategy for new molecules must begin well in time to produce comparable product. The project is specifically aimed at huge global market. Recommended for approval. 11. Name & Designation (in BLOCK LETTERS) 11.1 Guide Prof. Dr.R.S THAKUR Professor and Head Department of Pharmaceutics Krupanidhi College of Pharmacy Bangalore – 560035. 11.2 Signature of Guide (Mrs. ROHINI R. M.) K. SRINIVASU Dy. Manager Formulation and development, BAL PHARMA LIMITED, Bangalore-560 009. 11.3 Co-Guide 11.4 Signature of Co-Guide 11.5 Head of the Department Prof. Dr.R.S THAKUR Professor and Head Department of Pharmaceutics Krupanidhi College of Pharmacy Bangalore – 560035. 11.6 Signature of HOD: 12. 12.1 Remarks of the Principal: 12.2 Signature of the Principal Prof. Dr. AMIT KUMAR DAS PRINCIPAL Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore – 560035. 9