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ENCLOSURE – I 6) BRIEF RESUME OF THE INTENDED WORK 6.1) NEED FOR THE STUDY Azithromycin (AZI) is a semi-synthetic, acid stable erythromycin derivative. It plays a leading role in the treatment or prophylaxis of common respiratory tract infections, skin infection and several other clinical diseases, such as opportunistic infections in AIDS, toxoplasmosis, paediatric infections, urethritis, middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis etc. However, the clinical application of azithromycin is limited by its low bioavailability as a result of its poor solubility in water and poor gastrointestinal response1. And, oral treatment of this drug is often associated with various adverse effects related to the gastrointestinal tract cramping, diarrhoea, nausea abdominal pain and vomiting2. Microencapsulation for oral use has been employed to sustain the drug release, and to reduce or eliminate gastrointestinal side effects3. In addition, multiparticulate delivery systems spread out more uniformly in the gastrointestinal tract. Various swellable polymers, hydrophobic polymers etc., are used frequently as matrices or coating materials for sustained or controlled release dosage forms4,5. Hence the present study is undertaken to formulate microspheres of azithromycin by using various polymers to achieve controlled release which may result in lower gastrointestinal side effects of the drug. Further it is planned to study the various factors influencing the release of drug from the microspheres such as biodegradation kinetics of the polymers, polymer molecular weight, polymer to core ratio etc. ENCLOSURE – II 6.2) REVIEW OF LITERATURE Zhang Z et al6 prepared and evaluated azithromycin (AZI) microcapsules based on hollow polyelectrolyte (PE) microcapsules by layer-by-layer self-assembly onto the surface of silica microsphere (SiO2). The prepared AZI/PE microcapsules with an average diameter 1.2m possessed homogeneous size and regular spherical shape. FTIR spectra and XRD patterns indicated that AZI molecular structure was not changed and AZI crystal state changed from monohydrate to dihydrate. The drug invitro release experimental results showed an obvious improvement in the dissolution rate of the prepared AZI/PE microcapsules in comparing with AZI raw material drug powder. Gao Y et al7 prepared and studied microspheres of roxithromycin with eudragit S100 and silica by the emulsion solvent diffusion method to mask the bitter taste of the antibiotic. The effect of different polymers and drug–polymer ratios on the taste masking and the characteristics of the microspheres were investigated. It was found that Eudragit S100 was the best for masking the unpleasant taste of roxithromycin among the six kinds of polymers investigated. The influence of other formulation factors, i.e. dichloromethane–acetone ratios and silica–polymer ratios on the properties of the microspheres were also examined. Ganza-Gonzaalez A et al8 designed and investigated the usefulness of chitosan and chondroitin sulphate microspheres for oral controlled release of metoclopramide hydrochloride in oral administration. Microspheres were prepared by spray drying of aqueous polymer dispersions containing the drug and different amounts of formaldehyde as cross-linker. Drug release kinetics was investigated in vitro in media of different pH. Chondroitin sulphate microspheres scarcely retarded drug release, regardless of crosslinker concentration and medium pH, and were thus not further characterized. Chitosan microspheres prepared with more than 15% formaldehyde (w/w with respect to polymer) showed good control release (more than 8 h), and release rates were little affected by medium pH. Release from chitosan microspheres prepared with 20% formaldehyde was independent of pH, suggesting that this may be the most appropriate formulation. The kinetics of drug release from chitosan microspheres were best fitted by models originally developed for systems in which release rate is largely governed by rate of diffusion through the matrix. Rastogi R et al9 studied isoniazid (INH) microspheres produced by a modified emulsification method using sodium alginate as the hydrophilic carrier. Particle sizes of both placebo and drug-loaded formulations were measured by SEM and the particle size distribution was determined by an optical microscope. The physical state of the drug in the formulation was determined by DSC. The release profiles of INH from microspheres were examined in simulated gastric fluid (SGF pH 1.2) and simulated intestinal fluid (SIF pH 7.4). Gamma-scintigraphic studies were carried out to determine the location of microspheres on oral administration and the extent of transit through the gastrointestinal tract (GIT). Concentration of the cross-linker up to 7.5% caused increase in the entrapment efficiency and the extent of drug release. Optimized isoniazid-alginate microspheres were found to possess good bioadhesion (72.25±1.015%). The bioadhesive property of the particles resulted in prolonged retention in the small intestine. Microspheres could be observed in the intestinal lumen at 4 h and were detectable in the intestine 24 h post-oral administration, although the percent radioactivity had significantly decreased (t1/2 of 99mTc = 4–5 h). Sinduri P and Purushotaman M10 prepared and evaluated norfloxacin sustained release microspheres using various polymers like carbopol 934, sodium carboxy methyl Cellulose in different drug:polymer ratios by using multiple emulsion solvent evaporation technique. Microspheres were evaluated for parameters like angle of response, bulk density, particle size, drug content in microspheres, drug loading, encapsulation efficiency and Invitro drug release studies. The prepared microspheres of norfloxacin showed sustained release of drug from the formulation for a period of 12 hours. ENCLOSURE-III 6.3) OBJECTIVES OF THE STUDY The present work is planned with the following objectives: • To prepare microspheres containing azithromycin by suitable microencapsulation technique using different polymers. • To evaluate the prepared microspheres for drug content, encapsulation efficiency, surface morphology by SEM analysis, size analysis, swelling property and in vitro drug release studies. • To investigate the possibility of interaction between the combination of polymers and also between polymers and drugs by FTIR. • To study the effect of different compositions of polymers on the drug release profile. ENCLOSURE – IV 7) MATERIALS AND METHODS 7.1) SOURCE OF DATA The primary data will be collected by conducting various experiments and investigations in the laboratory and recording the observations. The secondary data will be collected by referring various national and international journals, books, Pharmacopoeia’s and professional websites like Helinet, Pubmed etc. ENCLOSURE–V 7.2) METHOD OF COLLECTION OF DATA 1. Instruments like dissolution apparatus, UV spectrophotometer will be used to record the observations. 2. Drug-polymer interaction will be investigated by using analytical techniques such as DSC, FT-IR etc. 3. Various polymers (hydrophilic and hydrophobic) such as chitosan, carbopol 934, eudragit RL 100, eudragit RS 100, ethyl cellulose, carnauba wax etc., will be used to fabricate microspheres containing the model drug in different drug:carrier ratios by adopting suitable techniques. 4. The prepared microspheres shall be characterized for their physicochemical properties using standard techniques. 5. In vitro release profiles of drug in simulated physiological fluid will be studied using USP dissolution apparatus. The in vitro data shall be analysed statistically and kinetics of drug release shall be studied. ENCLOSURE –VI 8) LIST OF REFERENCES 1. Zhang DR, Tan TW, Gao L, Zhao WF, Wang P. Preparation of azithromycin nanosuspensions by high pressure homogenization and its physicochemical characteristics studies, Drug Dev Ind Pharm 2007;33:569-575. 2. Dunn CJ, Barradell LB. Azithromycin: a review of its pharmacological properties and use as 3-day therapy in respiratory tract infection. Drugs 1996;51:483-505. 3. Kondo A. Microcapsule Processing and Technology, Marcel Dekker, New York, NY, 1979. 4. Harland RS, Gazzaniga A, Sangalli ME, Colombo P, Peppas NA. Drug/polymer matrix swelling and dissolution. Pharm Res 1988;5:488-494. 5. Chitnis VS, Malshe VS, Lalla JK. Bioadhesive polymers-synthesis, evaluation and application in controlled release tablets. Drug Dev Ind Pharm 1991;71:879-892. 6. Zhang Z, Zhu Y, Yang X, Li C. Preparation of azithromycin microcapsules by a layer-by-layer self-assembly approach and release behaviors of azithromycin. Colloids and Surfaces A: Physicochem Eng Aspects 2010;362:135-139. 7. Gao Y, Cui F, Guan Y, Yang L, Wang Y, Zhang L. Preparation of roxithromycinpolymeric microspheres by the emulsion solvent diffusion method for taste masking. Int J Pharm 2006;318:62-69. 8. Ganza-Gonzaalez A, Anguiano-Igea S, Otero-Espinar FJ, Blanco Meandez J. Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide. Eur J Pharm and Biopharm 1999;48:149-155. 9. Rastogi R, Sultana Y, Aqil M, Ali A, Kumar S, Chuttani K, Mishra AK. Alginate microspheres of isoniazid for oral sustained drug delivery. Int J Pharm 2007;334:7177. 10. Sindhuri P, Purushotaman M. Formulation and evaluation of norfloxacin microspheres using different polymers. Int J Pharm & Ind Res 2011;1(1):32-35.