FORMULATION OF SUSTAINED DELIVERY SYSTEM AND BIOPHARMACEUTICAL ANALYSIS OF BIODEGRADABLE AND NON-BIODEGRADABLE MICROPARTICLES LOADED WITH MODEL SOLUTES

Abstract

This research project deals with the elaboration and evaluation of coacervation technique for the microencapsulation of single drug (nimesulide) and/or in combination (nimesulide and tizanidine) using non-biodegradable and biodegradable polymers and physicochemical evaluation of prepared Aims and objectives microparticles. The coacervation inducing methods adopted were temperature change, pH change and non-solvent addition. The polymers employed were non-biodegradable (ethylcellulose and hydroxypropylmethylcellulose) and biodegradable [Chitosan and poly(lactide-o-glycolic acid)]. Various microparticulate formulations were prepared by varying the ratio of drug to polymer. Firstly, EC microparticles were prepared using coacervation technique induced by temperature change, to sustain the release of nimesulide and study the effect of various formulation variables. Secondly, floating microparticles of nimesulide using HPMC were prepared via coacervation non-solvent addition technique to provide a mean of getting low dosage for prolonged periods and to avoid direct contact with mucosa to minimize the irritant effect of drug on the stomach. Thirdly, nimesulide-chitosan microparticles were prepared by pH change coacervation by using cross-linking agent glutaraldehyde. Fourthly, nimesulide was also formulated as sustained release microcapsules using biodegradable polymer PLGA as the retardant material by non-solvent addition coacervation method. Fifthly, nimesulide was formulated as novel dual coated microparticles using chitosan and EC as encapsulating materials for its improved delivery to the intestine and to prevent gastric irritation and to increase compliance of patient. For dual coating, the coacervation techniques adopted for CTN and EC were pH change and thermal change, respectively. Sixthly, the microparticles for concurrent delivery in combined dosage of nimesilde and tizanidine to maintain a constant therapeutic concentration in plasma that may increase patient’s compliance and to improve the efficacy were prepared using coacervation-thermal change technique. The prepared microparticles with different drug/polymer ratios were characterized by micromeritics, SEM, FTIR, XRD, dissolution and thermal studies. In-vitro, release profiles of prepared microparticles were studied using USP XXIV dissolution apparatus I and II, respectively in 900 ml phosphate buffer pH 6.8 at 75 rpm maintained at 37°C. Release profiles were evaluated by model-dependent as well as model independent approaches. Aims and objectives High Performance Liquid Chromatography was used for in-vivo studies of marketed tablets and EC (with residual concentration very below toxic level for cyclohexane and n-hexane) and chitosan microparticles (with residual concentration very below for glacial acetic acid and glutaraldehyde). A reverse phase C18 column was used. The mobile phase composition was acetonitrile- methanol-15 mM potassium dihydrogen phosphate buffer (30:20:50), the buffer pH was adjusted with potassium hydroxide to 7.8. It was passed through a 0.4 μm filter before use. The flow rate was 1 ml/min at 30 oC and run time was 7 minutes. The detection was performed at 404 nm. Finally, the in-vitro in-vivo correlations (IVIVC) were established between the in-vitro and in-vivo data obtained from EC and chitosan formulations using Wagner-Nelson equation. All microparticles were discrete, yellowish in colour and irregular in morphology with good stability, fine rheological properties and good encapsulation efficiencies. Percentage product yields were greater than 80% for EC and HPMC formulations. No strong chemical interaction was observed in between drug and polymers as evident from FTIR, XRD and thermal analyses. It was found that release behaviour was biphasic and directly proportional to polymer concentration. According to the plots linearity drug release profile from all the formulations was explained in the order Higuchi’s equation > zero order > first order. The method of drug release from all formulations was anomalous diffusion. It was found that pH change coacervation is an efficient method to encapsulate biopharmaceutical class II drugs into different polymers like EC, HPMC, chitosan and PLGA. The EC formulations (M1 and M2) and conventional tablet (Nimarin®) exhibited good linear IVIVC (R2 = 0.9220, 0.9124, 0.8728, respectively) as compared to M3 (R2 = 0.9449). The results substantiate the success of this mathematical simulation study and encourage researchers to conduct biowaiver studies for other BCS class II drugs. The regression coefficients of IVIVC plots for chitosan formulations (M1, M2, M3) and conventional tablet were 0.8611, 0.9223, 0.9328 and 0.904, respectively.