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Development Of Sustained Release Formulations Of Procainamide Hydrochloride For Oral Use (Microcapsules)

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Microencapsulated forms of procainamide hydrochloride (PA) were formulated and evaluated for in vitro release against Procan SR('R) tablet. Both ethylcellulose as well as Eudragit-S microcapsules were prepared by a phase separation coacervation technique. The ethylcellulose or Eudragit-S coat-to-core (PA) ratios studied were 1:1, 1:1.33, 1:2 and 1:4, while the coat-to-polyethylene ratios investigated were 3:1, 5:1, 10:1 and 30:1. Treatment of microcapsules with four different concentrations (5, 10, 15 and 20% w/v) of paraffin wax in cyclohexane was also evaluated for effects on drug release. Ethylcellulose microcapsules and Eudragit-S microcapsules with coat to core ratio of 1:4 and 1:2 respectively and a coat-to-polyethylene ratio of 30:1, after treatment with 5% paraffin wax solution, were selected for a biphasic in vitro release study in hydrochloric acid buffer, pH 1.2 for first hour, and phosphate buffer, pH 7.8 for the remaining period. The mixed blends of ethylcellulose and Eudragit-S microcapsules in the proportions of their PA content were also considered for biphasic in vitro release study. While ethylcellulose microcapsules were insensitive to pH changes, Eudragit-S microcapsules gave faster drug release in phosphate buffer pH 7.8 as expected. The time for release of 50% PA was 2.05, 5.85, 2.30, 2.70, 3.00 and 3.90 hours for Procan SR tablets, ethylcellulose microcapsules, Eudragit-S microcapsules, mixed blends MX-1, MX-2 and MX-3 respectively. The ethylcellulose microcapsules (XXI) and mixed blend (MX-3) provided more effective sustained release of PA over several hours than commercially available product Procan SR tablets. Three promising formulations (XXI, XXII and MX-3) were further evaluated for in vivo bioavailability in dogs. On the basis of area under the plasma concentration-time curve (0-10 hrs.) and total cumulative amount of drug excreted (0-30 hrs.), three formulations were found to be bioequivalent to Procan SR('R) tablets. The plasma concentration-time curve data for each formulation was analyzed pharmacokinetically by an open, one-compartment model. Mechanism of drug release from these microcapsules was also studied. The analysis of in vitro release data strongly suggests a diffusion-controlled release of PA from ethylcellulose microcapsules and possibly Procan SR tablets. The release of PA from Eudragit-S microcapsules was shown to be dissolution-controlled.

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