DEVELOPMENT AND PHARMACOKINETICS OF A NEW SUSTAINED-RELEASE FORMULATION OF DILTIAZEM

Among the antihypertensive agents, calcium antagonists and in particular diltiazem play a leading role. To improve the conditions of diltiazem administration in the treatment of hypertensive patients a galenic formulation allowing administration of a single daily dose has been developed. The studies discussed in the following are concerned with the pharmacotechnical and pharmcokinetic development of sustained-release microgranules (sustained-release diltiazem). Bioavailability studies were performed after single-dose administration and after repeated-dose administration which were compared to the conventional formulation of diltiazem, Tildiem. After single-dose administration the following results were achieved: a relative bioavailability of 1.06 +/- 0.35; a prolongation of t(max) of 7.16 +/- 2.66 vs. 2.46 +/- 0.80 h; and a longer final half-life of 11.8 +/- 5.3 vs. 5.6 +/- 1.1. After repeated administration of sustained-release diltiazem at a single daily dose of 240 mg compared to repeated administration of the conventional formulation of diltiazem at doses of 120 mg every 12 h over a period of 6 days, the following results were obtained: a relative bioavailability of 0.90 +/- 0.17; a lowering effect on C(max) of 191 +/- 65 vs. 230 +/- 95 ng/ml; statistically equivalent minimum concentrations of 62 +/- 21 ng/ml vs. 74 +/- 33 ng/ml. In an additional study, the effect of concurrent food intake on the bioavailability of diltiazem was confirmed. An increase in bioavailability of 28% in combination with an increase in interindividual variability was observed. The development of microgranules allowing controlled diffusion of the drug made it possible to develop a sustained-release formulation of diltiazem at a dose of 300 mg, which yields effective and well-tolerated concentrations (80-200 ng/ml) with a single daily dose regimen.