Novel formulations of dipyridamole with microenvironmental pH-modifiers for improved dissolution and bioavailability under hypochlorhydria.

Chika Taniguchi, Ryo Inoue, Yohei Kawabata, Kazuhiro Yamashita, Koichi Wada, Yukinori Yamauchi, Shizuo Yamada, Satomi Onoue

Index: Int. J. Pharm. 434(1-2) , 148-54, (2012)

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Abstract

This study was undertaken to develop new dipyridamole (DP) formulations with acidic microenvironmental pH-modifiers for improving dissolution and absorption under hypochlorhydric conditions. Dipyridamole granules (DPG) with ten acidic pH-modifiers were prepared with conventional wet granulation, and their manufacturability, stability and dissolution behavior were characterized. Pharmacokinetic profiling of the optimized DPG with acid was carried out in omeprazole-treated rats as a hypochlorhydric model. On the basis of the manufacturability, stability and dissolution behavior of new DPG formulations, p-toluenesulfonic acid (TS) was found to be a suitable acidic pH-modifier for DPG formulation. Although DPG showed pH-dependent dissolution behavior, DPG with TS exhibited a high rate and extent of dissolution in both acidic and neutral media. After oral administration of DPG (10mg DP/kg) in omeprazole-treated hypochlorhydric rats, there was ca. 40% reduction of the area under the curve of plasma concentration vs. time from zero to 3h (AUC(0-3)) for DPG compared with that in normal rats. However, AUC(0-3) for DPG/TS under hypochlorhydria was almost identical to that of DPG in normal rats. From these findings, the addition of TS as a microenvironmental pH-modifier in DP formulation might be beneficial in expanding the therapeutic potential of DP in hypochlorhydric patients.Copyright © 2012 Elsevier B.V. All rights reserved.