New Dipyridamole Salt with Improved Dissolution and Oral Bioavailability under Hypochlorhydric Conditions

抄録

  The aim of this study was to develop new dipyridamole (DP) salts with pH-independent solubility for improving oral bioavailability under hypochlorhydria. Salt screening was carried out using nine counterions by the temperature gradient method. Six DP salts were obtained, and there was marked improvement in dissolution behavior for all DP salts in a neutral medium. Most DP salts were stable under accelerated conditions. On the basis of the dissolution and stability data, DP tosylate (DP/TS) was selected as a promising DP salt. Pharmacokinetics of DP and the promising DP salt were assessed in normal rats and omeprazole-treated rats as a hypochlorhydric model. After oral administration of DP/TS (10 mg-DP/kg) in normal rats, enhanced DP exposures with increased C_max and AUC_0-3 were observed compared with those with DP by ca. 2.8- and 1.7-fold, respectively. There was ca. 1 h delay of T_max and ca. 62% reduction of AUC_0-3 for DP in omeprazole-treated rats compared with those for DP in normal rats; however, oral absorption for DP/TS under hypochlorhydria was almost identical to that in normal rats. The newly developed DP/TS might provide better therapeutic efficacy in clinical use for hypochlorhydric patients.