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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

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NAME OF THE CANDIDATE AND ADDRESS:

Permanent address JAYA SHANKARA A.L S/O Lakshaminarayanappa Ankathatty (V) Mathnahalli (P) Kolar Taluk, Kolar District-563101 Karnataka Postal address Krupanidhi college of Pharmacy, Chikka Bellandure, Carmelaram Post, Varthur Hobli, Bangalore-560035 Karnataka

2.

NAME OF THE INSTITUTE:

Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore 560035, Karnataka MASTER OF PHARMACY IN PHARMACEUTICAL TECHNOLOGY 7th July 2010

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COURSE OF THE STUDY & SUBJECT: DATE OF ADMISSION TO THE COURSE: TITLE OF THE TOPIC:

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FORMULATION AND EVALUATION OF FAST RELEASE CAPSULES OF AN ANTI-DIABETIC DRUG USING SEMI SOLID MATRIX FILLING TECHNIQUE

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BRIEF RESUME OF THE INTENDED WORK:

6.1 Need of Study: Diabetes mellitus is a common and increasing health problems associated with marked morbidity and mortality rate. Diabetes mellitus is characterized by constant high levels of blood glucose1. Diabetes mellitus is a disorder of glucose metabolism that results from an absolute or relative lack of insulin and it shows complication of accelerated atherosclerosis, retinopathy and nephropathy. Hereditary traits, age, poor diet, stress, drugs, infections, hypertension are the major causes of diabetes2. The survey of International Diabetes Federation in 2007, reported that India was a country with the largest numbers of people with diabetes cases of 40.9 million. The statistics shows the mortality for diabetes is at the rate of one person for ten seconds. As per the survey report the new cases of diabetes by the year 2025 many reach 7 million in the world3. Anti-diabetic drugs such as glipizide, repaglinide, pioglitazone & glibencamide are reported to posses less dose, poor aqueous solubility with possible content uniformity problems. The poor aqueous solubility of these drugs shows absorption problems and its dissolution rate is considered to be the rate limiting step for absorption. During high blood glucose level conditions, an anti-diabetic drugs should show quick and high oral bioavailability which can be achieved by improving the solubility and rate of dissolution4. Semi Solid Capsule filling is a novel method to incorporate liquid solution or suspension of drug in to a hard gelatin capsules using a hydrophilic carriers. In this method as the drug is dispersed molecularly in hydrophilic carriers, it results in the enhancement of solubility and dissolution rate. Studies reported the improved rate of dissolution of Nimodipine semi solid capsules by using plasdone as polymer 5.Semi solid matrix filling into hard gelatin capsules is a new technique is being used more

often because it has several advantages such as weight and content uniformity, improvement in the dissolution of poorly water-soluble drugs and creation of dustfree manufacturing process with minimal number of manufacturing steps5. Literature survey revealed that several techniques such as solid dispersion, complexation, solubilizaion, particle size reduction etc has employed for dissolution enhancement of anti diabetic drugs. Studies reported that an improvement of solubility & dissolution rate for glibenclamide semi solid matrix filled capsules using hydrophilic carriers like tetraglycol & gelucire6. Another study reported enhancement of solubility and dissolution of glipizide using different solubilization techniques7. Formulation of low dose drug can be very challenging due to content uniformity problems which can overcome by selecting suitable hydrophilic additives excipients & there by formulating homogenous low dose formulation8. In the present work we are making an attempt to improve solubility, dissolution rate of an anti-diabetic drug employing semi solid matrix capsule fill technology in hard gelatin capsules and to evaluate the optimized formulation. 6.2 Objective of Study: The main objective of the present study is to enhance the dissolution rate of poorly aqueous soluble drugs. To highlight this study liquid fill technology is employed to prepare fast release capsule of an anti-diabetic drug using a hydrophilic carrier. The individual objective to be achieved include, 1. Selection of any one of the suitable water insoluble anti-diabetic drugs like Glipizide, Repaglinide, Metformin & Pioglitazone etc. 2. Screening of the polymer and other excipients to be used in the formulation are hydrophilic surfactants or polymers like Tween, Poloxamer, PEG and Gelucire. 3. Preformulation compatibility studies on the drug and excipients. 4. Study of the physiochemical characteristics of the formulation.

5. Formulations of semi-solid matrix by liquid fill technology. 6. Evaluation studies like drug content, dissolution studies, moisture uptake studies, solubility studies and thermal studies. 7. Accelerated stability profile as per ICH guidelines.

6.3 Review of Literature: Seven Stegemann et al., provides an overview of the benefits for filling of two piece hard gelatin capsules with liquid. The processes have also been proven to be commercially viable for in-house manufacturing9. Ewart T. Cole et al., described the use of hard gelatin capsules as an alternative for liquid/semi solid formulation. A screening program has been described from which a list of functional excipients compatible with the gelatin shell can be listed. The process can be scaled-up and also kept in-house in a manner similar to the operation of tableting or powder/pellet filling of hard gelatin capsules10. Prameela Rani. A. et al., studied the phase solubility on oral anti-diabetic drugs with -cyclodextrin and Hydroxypropyl--cyclodextrin. They have reported the improved solubility of Nateglinide, Repaglinide, & Glimepiride by complexation with cyclodextrin11. Adel M. Aly, et al., reported that enhancement of the dissolution rate and bioavailability of glipizide through cyclodextrin inclusion complex by using various carriers like PVP, NaCMC and PEG 6000. The formulation containing cyclodextrin and cyclodextrin derivatives have proved as effective solubilizer for glipizide12.

A. Smith et al., reported that dissolution rate of ibuprofen melt filled capsules was markedly affected by incorporation of low levels of a variety of excipients. The

different carriers used for the semisolid dispersion were PEG 400, 4000 and 6000, Acdisol, crosspovidone, Gelucire13. A.B Dennis et al., developed both rapid and sustained release formulation of ketoprofen. Rapid release was achieved by Gelucire 44/14 and prolonged release was achieved by Gelucire 50/13. The formulation on comparing with conventional showed similar plasma concentration14. S.K Cole et al., designed a semi solid matrix capsule filled formulation of vitamin E using non-ionic surfactants. The incompatibility occurring with non-ionic surfactant in hard gelatin capsules was over come by including glycerol and water. Dissolution and stability studies indicated efficient delivery of lipophilic drugs15. NiluferYuksel et al., investigated the invitro and invivo performance of the semi solid dispersion prepared with Gelucire 44/14 and Labrosol. The prepared semisolid dispersion showed higher dissolution rate compared with pure piroxicam and a commercially available tablets dosage form containing a piroxicam cyclodextrincomplex16. Barakat N.S et al., designed enteric coated liquid filled hard gelatin capsules of propranol. It had a characteristic of biphasic rapid and sustained release with out hepatic first-pass metabolism. Dissolution studies were carried out at both basic and acidic pH, Significant alteration in release was achived17. A Kattige et al., lactose/poloxamer dispersion exhibited thixotropic shear thinning behaviour with an abrupt increase in apparent viscosity above a limiting concentration of disperse phase. The rheological data was analyzed in detail using empirical models and also used to identify capsule filling problems18

Ewart T Cole et al., encapsulation of liquid and semi solid provides solutions for convenient delivery through improved oral absorption of poorly water soluble drugs, low dose, highly potent, and low melting point drugs19.

N.S Barakat et al., formulated liquid filled dispersion of etodolac in hard gelatine capsule using gelucire with an approach to increase the dissolution rate and stability of poorly soluble drug. E.L Massik M.A et al., semi solid fill bases were selected for the formulation of a capsule. The filled material includes lipophilic bases and hydrophilic bases. The dissolution rate study indicated that formulation contains lipophylic and hydrophilic bases showed the best release profiles21. 7. Materials & Methods: 7.1 Source of Data: Data will be obtained from 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 Drug Information Centers. 7.2 Method of Collection of Data (including sampling procedure, if any): The physiochemical properties of the drug will be collected from drug information centre. Various standard books journals websites and other sources like research literature databases like medline, sciencedirect, pubmed are followed. The experimental data will be collected from the study of drug and literature. Its formulation was done through investigation of process and product variables are evaluated in laboratory of Krupanidhi college of pharmacy Bangalore.

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 and finally the system was evaluated. The steps involved in the methodology is 1 2 Selection of suitable anti-diabetic drug (Repaglinide or Glipizide or Metformin or Pioglitazone) Selection of the polymer and other excipients to be used in the formulation are hydrophilic surfactants and polymers like Tween, Poloxamer, PEG and Gelucire. 3 4 5 6 7 Preformulation studies on the drug and excipients. Formulation of semi solid matrix by liquid fills Technology. To carry out in vitro evaluation of various formulations. Optimization of the dosage form based on evaluated parameters. To carry out accelerated stability profiling as per ICH guidelines.

7.3 Method of Screening: z7.3 Does the study require any investigations or interventions to be conducted on patients or other human or animals? If so please describe briefly: -NO7.4 Has the Ethical Clearance been obtained from your Institution in case of 7.3?

-NOT APPLICABLE-

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LIST OF REFERENCES:

1)Lippincott, Williams & Wilkins. Remington. The science and practice of pharmacy. 21st ed. B.I publications, 2006;1:1125. 2)Williams G. Management of non-insulin dependent diabetes mellitus. Lancet 1994; 343:95-100.Available From: URL://www.ncbi.nlm.nih.gov/pubmed/7903785 [Access date: Nov 18] 3)Diabetes Statistics: India Is The Diabetes Capital Of The World 2008 Feb 25. Available From: URL:http://health.savvy-cafe.com/diabetis-statistics-india-is-the-diabetic-capital-of -the-world-2008-02-25 [Access date: Nov 23] 4)D Choudhary, S Kumar, GD Gupta. Enhancement of solubility and Dissolution of glipizide by solid dispersion (kneading) technique. Asian J Pharm 2009 Jul-Sep:245-51. 5)Sun Yunzhe, Yang Rui, Zhou Wenliang, Tang Xing. Nimodipine Semi-solid capsules containing solid dispersion for improving dissolution.Int J Pharm Sci 2008;359:144-9. 6)Saly Galal, MagdaEL-Massik, Ossama Abdallah, Nabila Daabis. Formulation of fast release glibenclamide liquid and semi-solid matrix filled capsules. Acta Pharm 2003;53:57-64. 7)Meenakshi Shukla, Priyanka Rathore, Ashish Jain, Satish Nayak. Enhanced Solubility Study Of Glipizide Using Different Solubilization Techniques. Int J Pharm Pharm Sci 2010;2(2):46-8. 8)Vipin Kukkar, Vikas Anand, Mahesh Kataria, Manoj Gera, Pratim Kumar Choudhury.Mixing and formulation of low dose drugs: underlying problems and solutions. Thai J Pharm Sci 2008;32:43-58.

9)Matt Richardson, Sven Stegemann. Filling Two- Piece Hard Gelatin Capsules With Liquids. Tablets & Capsules 2007 Jan.Available From: URL://www.Capsugel.Com/pdf/Filling-Two-Piece-Hard-Gelatin-Capsules-WithLiquids.pdf 10)Ewart T Cole. Liquid filled and sealed hard gelatin capsules. Capsugl Library, Warner-Lambertco, Switzerland;1-12. URL: http://www.capsugel.com/pdf/brochure_liquid.pdf 11)Prameela Rani A, Siva Teja P, Archana N, BalaSekaran C. Phase Solubility Studies On Oral Anti-diabetic Drugs with beta-Cyclodextrin and HP-beta Cyclodextrin. Int J Pharm Tech Res 2009 Oct-Dec;1(4):1632-7. 12) Adel MAly,Mazen K Qato, Mahrous O Ahmad. Enhancement of the Dissolution Rate and Bioavailability of Glipizide through Cyclodextrin inclusion Complex. Pharm Tech 2003 June:54-62. 13) A Smith, JF Lampard, KM Carruthers, P Regan. The filling of Molten ibuprofen into hard gelatin capsules. Int J Pharm 1990;59(2):115-9. 14) AB Dennis, SJ Farr, IW Kellaway, G Taylor, R Davidson. In vivo evaluation of rapid release and sustained release Gelucire capsule formulation. Int J Pharm 1990;65(1-2):85-100. 15)SK Cole, MJ Story, D Attwood, T Laudanski, J Robertson, SG Barnwell. Studies using a non-ionic surfactant-containing drug delivery system designed for hard gelatin capsule compatibility. Int J Pharm 1992 Dec 8;88(1-3):211-20. 16)Nilufer Yuksel, Aysequl Karata, Yalcm Ozkan, Ayhan Savaer, SibelA.Ozkan, Tamer Bayakara. Enhanced bioavailability of piroxicam using Gelucire 44/14 and Labrosol. Eur J Pharma 2003;56(3):453-9.

17)SJ Burns, S Higginbottonm, D Corness, G Hay, I Whelan, D Attwood et al. A study of enteric-coated liquid-filling hard gelatin capsules with biphasic release characteristics. Int J Pharm 1994;110:291-6. 18)A Kattige, G Rowley. Influence of rheological behaviour of particulate polymer dispersion on liquid-filling characteristic for hard gelatin capsules. Int J Pharm 2006Jun26;316(1-2):74-85. 19)Ewart T Cole, Dominique, Cade, Hassan Benameur. Challenges and opportunities in the encapsulation of liquid and semi-solid formulation into capsules for oral administration. Adv Drug Deliv Reviews 2008Mar17;60(6):747-58. 20)NS Barakat. Etodolac-liquid-filled dispersion into hard gelatin capsules: An approach to improve dissolution and stability of etodolac formulation. Letters in Drug Desi Discov 2009;32:865-76. 21)EL Massik MA, Abdallah Oy, Galals, Daabis NA. Semi-solid matrix filled capsules: An approach to improve dissolution stability of phenytion sodium formulation. Drug Dev Ind Pharm 2003;29(5):531-43. 9. Signature of the Candidate

(JAYA SHANKARA A L) ((Rajesh

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Remarks of the Guide:SjjjjjjjjIS OF SOME NOVEL DERIVATIVES OF S Liquid formulations filled into two-piece hard capsules have attracted substantial interest in the pharmaceutical industry over the last decade. Todays challenges in product development due to the poor aqueous solubility and high potency of the new molecular entities are being addressed by several development groups that are focused on liquid or semi-solid formulations. As filling and sealing of these formulations into two-piece hard gelatin capsules can be done easily in-house with improved rate of dissolution. Hence it is recommended for necessary clearance. ELENO-o987lQUINAZOLONE AND EV ALUATION OF THEIR ANTIOXIDANT AND ANTIMICROBIAL ACTIVITY to c Mr. Rajesh Name & Designation (in BLOCK LETTERS)

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11.1 Guide

Mrs. SARITHA ALLADI ASSISTANT PROFESSOR Department of Pharmaceutical Technology Krupanidhi College of Pharmacy, Bangalore-560035.

11.2 Signature of Guide (Mrs. ROHINI R. M.) 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 PharmaceuticaTechnology Krupanidhi College of Pharmacy Bangalore 560035.

11.6 Signature of HOD:

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12.1 Remark of the Principal:

12.2 Signature of the Principal

Prof. Dr. N. PREM KUKAR PRICIPAL Krupanidhi college of pharmacy, ChikkaBellandur, Carmelaram Post, Varthur Hobli, Bangalore 560035 Karnataka