Development and Evaluation of Sustained Release Dosage Form using Hydrophilic and Hydrophobic Materials

Abstract

Cephalexin is a first generation cephalosporin antimicrobial agent with activity against Gram negative microorganisms. Oral therapy with cephalexin results in peak concentration in plasma of 18 mcg/mL after a dose of 500 mg. The usual oral or parenteral antibiotic regimen results in high peak levels that fall well below therapeutic concentration before administration of next dose. For Cephalexin, the plasma concentration above 1.0 mcg/mL is above the MIC in vitro for most of the susceptible microorganisms. These characteristics coupled with the short biological half life of 1 hour suggest that it is a rational candidate for a sustained release dosage form. Based on the pharmacokinetics, the sustained release tablet containing 375 mg Cephalexin monohydrate should release 78.3 mg of cephalexin initially within first 1 h and 46.7 mg of cephalexin per hour for next 5 h of in order to maintain plasma cephalexin concentration of 4.5 mg/L. The sustained release tablets were prepared by wet granulation technique containing HPMC K4M, K15M, K100M, K100LV, ethyl cellulose, Carbopol, Eudragit RS 100, Eudragit RL 100, and Eudragit L100. In vitro release profiles of optimized cephalexin matrix tablets containing HPMC, carbopol and eudragit has shown sustained release up to 6 hours. It was observed that the release rate was slower with higher quantities and higher viscosities of HPMC. The rate of drug release was found in the order HPMC K100LV < K4M < K15M < K100M. The rate of drug release was slower in case of carbopol 974P than carbopol 971P. The drug release from tablets containing eudragit L100 (pH dependent) and eudragits RL100, RS100 (pH independent) was studied. An inverse relation was observed between release of cephalexin and quantity of Eudragit. Eudragit L100 being pH dependent, solubilises at pH above 6. It shows retardant effect in acidic pH for initial two hours and faster release in alkaline pH. Formulations containing HPMC K4, K5, K7and K10, the dominant mechanism for drug release through HPMC based matrix systems may be anomalous (non-fickian) transport. For formulations containing carbopol namely C3 and C7 indicating that drug was released by anomalous transport. On the other hand Eudragit L100 containing formulation (E3) Super case II transport was found to be the release mechanism from matrix system.