Rajiv Gandhi University of Health Sciences s191

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

M. PHARM SYNOPSIS

YEAR OF 15/05/2010

TITLE OF THE SYNOPSIS

FORMULATION AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF ANTI-DIABETIC DRUG

SIPAI ALTAF BHAI .M.

M.PHARM, PART- I

DEPARTMENT OF PHARMACEUTICS,

UNDER THE GUIDANCE OF

Mr. PRADEEP.S, M. PHARM

Asst. Professor

DEPARTMENT OF PHARMACEUTICS

INSTITUTION

GAUTHAM COLLEGE OF PHARMACY

R. T. NAGAR, BANGALORE-32, KARNATAKA

1 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 Name of the candidate and address SIPAI ALTAF BHAI. M.

PERMANENT ADDRESS S/O. Sipai Mohammed bhai .v. Behind jampura school, Maher society, PALANPUR-385001. BANASKANTHA, GUJARAT.

2 Name of the institution GAUTHAM COLLEGE OF PHARMACY, Bhuvnaeswari Nagar, Sultanpalya, R.T.NAGAR POST, BANGALORE – 560032.

3 Course of study and subject MASTER OF PHARMACY IN PHARMACEUTICS

4 Date of the admission 15/05/2010

5 Title of the topic:

“FORMULATION AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF ANTI-DIABETIC DRUG”

2 6.0 Brief resume of the intended work:

6.1 Need for the study:

For many decades, medication of an acute disease or a chronic illness has been accomplished by delivering drugs to the patients via various pharmaceutical dosage forms like tablets, capsules, pills, creams, ointments, liquids, aerosols, injectables and suppositories as carriers. To achieve and then to maintain the concentration of drug administered within the therapeutically effective range needed for medication, it is often necessary to take this type of drug delivery systems several times a day. This results in a fluctuated drug level and consequently undesirable toxicity and poor efficiency. This factor as well as other factors such as repetitive dosing and unpredictable absorption leads to the concept of controlled drug delivery systems.1-2

The objective of controlled release drug delivery includes two important aspects namely spatial placement and temporal delivery of drug.

1). Spatial placement relates to targeting a drug to a specific organ or tissue, while 2). Temporal delivery refers to controlling the rate of drug delivery to the target tissue.3

The objective in designing a controlled release system is to deliver the drug at a rate necessary to achieve and maintain a constant drug blood level. This rate should be analogous to that achieved by continuous intravenous infusion where a drug is provided to the patient at a rate just equal to its rate of elimination. This implies that the rate of delivery must be independent of the amount of drug remaining in the dosage form and constant over time. That is release from the dosage form should follow zero-order kinetics.4

Microsphere carrier systems made from the naturally occurring biodegradable polymers have attracted considerable attention for several years in sustained drug delivery. Recently, dosage forms that can precisely control the release rates and target drugs to a specific body site have made an enormous impact in the formulation and development of novel drug delivery Systems. Microspheres form an important part of such novel drug delivery systems.5-7

3 They have varied applications and are prepared using assorted polymers.8 However; the success of these microspheres is limited owing to their short residence time at the site of absorption. It would, therefore, be advantageous to have means for providing an intimate contact of the drug delivery system with the absorbing membranes.9-12 This can be achieved by coupling Bioadhesion characteristics to microspheres and developing bioadhesive microspheres. Bioadhesive microspheres have advantages such as efficient absorption and enhanced bioavailability of drugs owing to a high surface-to-volume ratio, a much more intimate contact with the mucus layer, and specific targeting of drugs to the absorption site.13-16 Gastric Mucoadhesive drug delivery offers a number of applications for drugs having poor bioavailability because of narrow absorption window in the upper part of gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability.17

Carbopol, chitosan, HPMC K 100 M and sodium alginate was selected as a polymer in the preparation of Mucoadhesive microspheres because of its good Mucoadhesive and biodegradable properties.18

Diabetes mellitus is a group of syndrome characterized by hyperglycemia, altered metabolism of lipids, carbohydrates, proteins and an increased risk of complication from the vascular disease.19

Metformin is an antihyperglycemic agent, which improves glucose tolerance in type II Diabetes. It has been reported that the absolute bioavailability of Metformin when given orally is 50.60%. Biological half life of Metformin is 1.5-1.6 h and the main site of its absorption is proximal small intestines.20-21 So, it required in large dose (1.5-2.0 g/ day) and it causes the incidence of GI side effect (30% cases).22 So, that development of oral controlled release dosage forms thus, would clearly advantageous.

Researchers have formulated oral controlled release products of metformin hydrochloride by various techniques.17,22

4 More ever, the site of absorption of metformin hydrochloride is in the proximal small intestine.20-21 Dosage forms that are retained in the stomach would increase the absorption, improve drug efficiency and decrease dose requirements. Thus an attempt is made in the present investigation to use carbopol and sodium alginate as a mucoadhesive polymer and prepare microspheres. The microspheres will be characterised by in vitro and in vivo tests and the factorial design will be employed to optimize the variables.

5 6.2 Main objectives of the study:

The primary aim of the proposed project is to develop Mucoadhesive microspheres of Metformin Hydrochloride.

In order to fulfill the aim the following objectives have to be met:

1. Selection of suitable polymers to develops the dosage forms. 2. Selection of suitable method for preparation of mucoadhesive Microspheres of metformin hydrochloride. 3. Study the compatibility of drug with various polymers. 4. Evaluation of prepared product. 5. Stability study of prepared product according to IGH guidelines.

The objectives of the proposed studies are as follows:-

1. To overcome the rapid elimination of drug and to develop the oral controlled drug delivery system. 2. To increase the biological half life of the drug or to maintain the constant drug concentration in the body.

6 6.3 Review of the literature: SACHIN.E.BHANKE, 3 Carried out study on formulation and evaluation of micro particles with Repaglinide as model drug for prolongation of drug release time. An attempt was made to prepare microparticles of repaglinide by ionotropic gelation techniques by using HPMC and Chitosan as a polymers.

CHOWDARY K.P.R.et al 16., Prepared ethyl cellulose microspheres of glipizide. In this study glipizide was incorporated into ethyl cellulose and were investigated by in vivo and in vitro methods.

YELLANKI SHIVA KUMAR.et al 17., Prepared mucoadhesive microcapsules of metformin hydrochloride using natural and synthetic polymers by using orifice gelation techniques utilizing calcium chloride as a cross linking agent. The microcapsules obtained was spherical, free flowing and exhibited good mucoadhesive properties and showed controlled drug release up to 10 hrs.

T.M.KALYANKAR.et al 18., Formulated and systematically evaluated in vitro performance of mucoadhesive microspheres of pioglitazone hydrochloride by orifice ionic gelation method using various polymers viz. sodium alginate , carbopol 934P, carbopol 971 NF, carbopol 974 NF, HPMC K100 M, and polycarbophil in different proportions. The microspheres obtained were spherical, free flowing and exhibited good mucoadhesive property with high percentage drug entrapment efficiency.

LIN L.Y.et al 24., Carried out the preparation of chitosan microspheres by an emulsion phase separation techniques and ionotropic gelation techniques. They reported that the prepared microsphere was spherical, free flowing and had smooth surface.

PATIL V.B.et al 25., Prepared and evaluated sustained release nimesulide microspheres from sodium alginate. In this investigation a 2³ full factorial design was used to study the joint influence of three variables such as The polymers concentration, Drug concentration and Cross linker concentration and some time various dependent variable like percent efficiency, sphericity, and particle size and drug release.

7 CHODAKE J.D.et al 22., Formulate and evaluate floating microspheres containing anti diabetic (metformin HCL) drug. The microsphere was prepared by emulsification solvent diffusion techniques using polymers like HPMC K 4 M and Eudragit RS100. The developed floating microsphere of metformin HCL may be used in clinic for prolonged drug release in stomach for at least 8 hrs, thereby improving the bioavailability and patient compliance.

S.K.SINGH.et al 26., Formulated and evaluated mucoadhesive microsphere of Amoxicillin trihydrate in management of H.Pylori infections. The microsphere was prepared by solvent evaporation method by using Eudragit RS 100, HPMC K4 M as mucoadhesive polymers. The drug content determination showed that even if the polymer composition was changed, the solvent evaporation process was highly efficient to give microspheres having maximum drug loading and prolonged gastrointestinal residence time.

DHAKAR R.C.et al 27., Sustained release mucoadhesive microspheres of metformin HCL were designed and evaluated to reduce the dosing frequency and to improve patient compliance for effective control of diabetes type-2 . Microspheres were prepared by emulsification solvent evaporation method using sodium carboxy methy cellulose(SCMC) ,carbopol 934P(CP) , and hydroxyl propyl methyl cellulose K4M(HPMC) , as a mucoadhesive polymers.The microspheres prepared were found discrete;spherical and free flowing .The microspheres exhibits good mucoadhesive properties and showed high drug entrapment efficiency.Metformin HCL released from this microspheres was slow and extended and dependent on the type of polymer used .Among all formulation ,formulation containing SCMC and CP showed the best reproducible results and mucoadhesive profile with good surface morphology.The obtained mucoadhesive microspheres can successfully design for sustained delivery of metformin HCL and to improve patient compliance.

VEENA BELGAMWAR.et al 28., Developed Mucoadhesive Multiparticulate System Of Metoprolol Tartarte For Oral drug Delivery using ionic gelation techniques. In this techniques cross linking of sodium alginate with calcium chloride was done which retarded the release of drug from the mucoadhesive polymers like HPMC of various grades like K4M,K15M,K100M,E50LV,Carbopol of grades 971P,974P and polycarbophil.The obtained microspheres were discrete,bulky, free flowing and showed an average

8 encapsulation efficiency ranging from 50-60% .The prepared microspheres formulation also exhibited a good mucoadhesive strength which was determined in in-vitro conditions through falling film technique and was compared with ex-vitro studies. The metoprolol microspheres released from the multiparticulate system was regulated and extended until 12h and exhibited a non-fickian drug release kinetics approching to zero order.

9 7.0 Materials and methods:

DRUG: Anti-Diabetic Drug (BCS CLASS-III).

POLYMERS: Sodium alginate Carbopol 934 P Carbopol 971 NF Carbopol 974 NF HPMC K 100 M Chitosan

OTHER CHEMICAL: Calcium chloride

METHOD: Orifice-Ionic Gelation Method.

7.1 Source of data:

Data will be obtained from Drug Invention Today, Pub med, Science Direct, Medline, US patent office website and other Internet facilities, literature search, and related articles from library of Gautham College of Pharmacy.

7.2 EVALUATION PARAMETERS:

1. Preformulation study. 2. Assay of metformin hydrochloride. 3. Drug entrapment efficiency. 4. Particle size determination. 5. Swelling index of microspheres. 6. In vitro WASH-OFF test for microspheres.(Rat mucosa) 7. Drug release study. 8. Scanning Electron Microscopy. 9. Accelerated stability studies. 7.3Does the study require any investigation or interventions to be Conducted on patients or other humans or animals? Yes. 7.4 Has ethical clearance been obtained from your institution in case of 7.3?

10 Yes. 8. List of References:

1. Yie W. Chien, "Concepts and System Design for Rate-controlled Drug Delivery", Chapter 1 in Novel Drug Delivery System', 2nd Edition, Marcel Dekker, Inc, New York,1992; l-42. 2. Yie W. Chien, 'Rate-controlled Drug Delivery Systems'. Ind. J. Pharm. Sci.1988; Mar-April: 63-65. 3. Sachine.E.Bhandke, “Formulation and Development of Repaglinide Microparticles By Ionotropic Gelation Techniques”.2006. 4. Thomas Wai-Yip Lee and Joseph R. Robinson, "Controlled / Release Drug-Delivery Systems", Chapter 47 in 'Remington's Pharmaceutical Sciences', 20th Edition, Mack Publishing Company.2000; 1: 903-929. 5. Woo B, Jiang G, Jo Y, DeLuca P. Preparation and characterization of composite PLGA and Poly (acryloyl hydroxyl methyl starch) microsphere system for protein drug delivery. Pharm. Res.2001; 18: 1600-1606. 6. Capan Y, Jiang G, Giovagnoli S, DeLuca PP. Preparation and characterization of poly (D, L-lactide-co-glycolide) microsphere for controlled release of human growth hormone. AAPS PharmSciTech.2003; 4:E28. 7. Gohel MC, Amin AF. Formulation optimization of controlled release diclofenac sodium microspheres using factorial design. J Control Release. 1998; 51:115-122. 8. Vasr JK, Tambwekar K, Garg S. Bioadhesive microspheres as a controlled drug delivery system. Int .J. Pharm.2003; 255:13-32. 9. Ikeda K, Murata K, Kobayashi M, Noda K. Enhancement of bioavailabity of dopamine via nasal route in beagle dogs. Chem Pharm Bull (Tokyo).1992; 40:2155- 2158. 10. Nagai T, Nishimoto Y, Nambu N, Suzuki Y, Sekine K. Powder dosage form Of insulin for nasal administration. J Control Release.1984; 1:15-22. 11. Ilium L, Farraj NF, Critechley H, Davis SS. Nasal administration of gentamicin using a Novel microsphere delivery system. Int .J. Pharm.1988; 46:261-265. 12. Schaefer MJ, Singh J. Effect of isopropyl myristic acid ester on the physical characteristics and in vitro release of etoposide from PLGA microspheres. AAPS PharmSciTech.2000; 1:E32.

11 13. Rao SB, Sharma CP. Use of chitosan as biomaterial: studies on its safety and hemostatic Potential. J Biomed Mater Res.1997; 34:21-28. 14. Lehr CM, Bouwstra JA, Schacht EH, Junginger HE. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymer. Int.J.Pharm.1992; 78:43-48. 15. Henriksen I, Green KL, Smart JD, Smistad G, Karlsen J. Bioadhesion of hydrated Chitosans: an in vitro and in vivo study. Int. J. Pharm.1996; 145:231-240. 16. Chowdary KPR, Rao YS. Design and in vitro and in vivo evaluation of mucoadhesive Microcapsules of glipizide for oral controlled release: a technical note. AAPS PharmSciTech.2003; 4:E39. 17. Yellanki shiva kumar, Deb sambit kumar, Goranti sharada, Nerella Naveen kumar.“Formulation Development Of Mucoadhesive Microcapsules Of Metformin HCL Using Natural And Synthetic Polymers And In vitro Characterization”.Int .J. Pharm.2010;2(2): 321-329. 18. T.M.Kalyankar, Nalanda T. Rangan, Mubeena khan, Avinash Hosmani and Arvind Sonwane. “Formulation And Evaluation Of Mucoadhesive Pioglitazone HCL Microspheres”.IJPWR2010; 1. 19. Lin L.Y., et al, Hydroxy propyl methyl cellulose in 'Hand Book of Pharmaceutical Excipients', Published by American Pharmaceutical Association and the Pharmaceutical Society of Great Britain,1986; 138-140. 20. L. Whitehead et al. Floating dosage forms: an invivo study demonstrating prolonged gastricretention. J Control Release.1998;55: 3.12. 21. Basak SC,et al. Design and in vitro testing of a floatable gastroretentive tablet of metformin Hcl.Pharmazie.2007; 62(2):145-148. 22. Ghodake J.D.,Vidhate J.S.,Shinde D.A., Kadam A.N. “ Formulation And Floating Microspheres Containing Anti-diabetic (Metformin HCL) Drugs.Int.J.PharmTech Res.2010; 2(1):378-384. 23. D. M. Brahmankar, Sunil B. Jaiswal., “Biopharmaceutics and Pharmacokinetics a Treatise”, First edition, Vallabh Prakashan Pitampura, Delhi-2001; 337-341. 24. Lim-Ly et. al. "Chitosan Microspheres Prepared by Emulsification of Ionotropic Gelation". Drug Develop. Ind. Pharm.1997; 23(10): 981-985.

12 25. Patil V.B. And Varsha B.Pokharkar. “Preparation And Evaluation Of Sustained Release Nimesulide Misrospheres Prepared from Sodium Alginate”. Ind.J.Pharm.Sci.2001; 63(1):15- 19. 26. S.K.Singh,V.R.Chaidrawar,Y.U.Ushir,K.R.Vadalia,N.R.Sheth,“pharmaceutical characterization of amoxicillin trihydrates as mucoadhesive microspheres in management Of h.pylori”.Int.J.PharmTech Res.2010;2(1):349-358. 27. Veena Belgamwar, Viral Shah and S.J.Surena. “Formulation and Evaluation of oral Mucoadhesive Multiparticulate system containing Metoprolol Tartarate:An In vitro- Ex vivo Characterization”.Current Drug Delivery.2009; 6:113-121. 28. Ramchand Dhakar, Sheo Dutta Maurya, Shweta Aggarwal, Girish Kumar, Vijay Kumar Tilak.“Design and Evaluation of SRM Microspheres of Metformin Hydrochloride”.Pharmacie Globale (IJCP).2010; 1(01):1-5.

13 9. Signature of the Candidate SIPAI ALTAF BHAI.M. ((Rajesh

10. Remarks of the Guide:

11. Name & Designation (in BLOCK LETTERS)

11.1 Guide MR.PRADEEP .S. Department of Pharmaceutics, Gautham College of Pharmacy, Bangalore – 560032. 11.2 Signature of Guide

Mrs. ROHINI R. M.) 11.3 Head of the Department Dr. SANJAY P. UMACHIGI. Prof & HOD Department of Pharmaceutics, Gautham College of Pharmacy, Bangalore – 560032 11.4 Signature of HOD:

12. 12.1 Remarks of the Principal: The program and the resea

rch work that Mr. Rajesh

14 12.2 Signature of the Principal Mrs. ARCHANA.P.SWAMY PRINCIPAL Gautham College of Pharmacy, Bhuvnaeswari Nagar, Sultanpalya, R.T.NAGAR POST, BANGALORE – 560032.