Abstract
The solubility of dipyridamole at pH 2.5 was about 6000-fold greater than that at pH 7.0. A commercial powder of dipyridamole showed pH-dependent dissolution. Two kinds of sustained-release granules of dipyridamole were prepared. The release rate of pH-dependent sustained-release granules was controlled by ethylcellulose (EC) and decreased with increasing medium pH. The release rate of pH-independent sustained-release granules was regulated by carboxymethylethylcellulose (CMEC), hydroxypropyl methylcellulose (TC-5) and Eudragit RS100, and was not influenced by varying pH of the medium. We used gastric-acidity-controlled rabbits to evaluate the variability in absorption after oral administration of these formulations. An extremely large difference in bioavailability between the high and low gastric acidity groups was observed after oral administration of the commercial powder. There were no statistically significant differences in the values of Cmax, Tmax, AUC0–12h and MRT between the high and low gastric acidity groups after administration of pH-independent sustained-release granules, while statistically significant differences in Cmax and AUC0–12 h were found between the two groups after administration of pH-dependent sustained-release granules. Furthermore, this pH-independent sustained-release granule preparation was administered orally to human subjects and compared with the commercial powder. There was no significant difference in the AUC0–12 h between the two preparations. It was also shown that the Cmax for the granules was about 50% of that for the commercial powder and that the plasma levels after oral administration of the granules were maintained over a longer duration than those of the commercial powder. It was found that the bioavailability was not influenced by variations in gastric acidity in rabbits and high bioavailability was achieved in human subjects after oral administration of the pH-independent sustained-release granule preparation, indicating that this preparation should be a useful dosage form for the potential reduction of interindividual variabilities in absorption.
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