DEVELOPMENT AND IN VITRO-IN VIVO EVALUATION OF A MULTIPARTICULATE SUSTAINED-RELEASE FORMULATION OF DILTIAZEM

Purpose. To develop and evaluate the in vitro/in vivo performance of d iltiazem sustained release pellets that were prepared by the Wurster c olumn process. Methods. Pellets containing diltiazem were prepared by spraying a slurry of micronized diltiazem hydrochloride, pharmaceutica l glaze and alcohol onto an appropriate mesh fraction of nonpareil see ds using the Wurster column. A two-step drug layering process was used to increase drug loading from 60% to 75%. The oven-dried diltiazem ba sic pellets were coated with ethylcellulose/dibutyl sebacate coating s olution to yield diltiazem sustained release pellets. An open, randomi zed Latin square. three-way crossover clinical study was used to evalu ate the in vivo performance of the coated product. Results. Altering t he mesh fraction of the starting nonpareil seeds for this layering pro cess was found to affect the release characteristics of drug from the pellets. An oven-drying step was required to stabilize the diltiazem b asic pellets. The thicker the drug loading layer the longer the oven d rying is needed to stabilize the pellets. The diltiazem sustained rele ase pellets produced by these methods displayed sustained release diss olution profiles both in vitro and in vivo. Diltiazem basic pellets co ated with a 0.6% ethylcellulose/dibutyl sebacate coating showed a diff erent rate of absorption (lower C-max and higher T-max) and the same e xtent of absorption as compared to Cardizem(R) tablets. Conclusions. C linical data confirmed that this formulation approach is an effective means to produce a diltiazem sustained release product.