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

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• 作者：Chika Taniguchi ; Ryo Inoue ; Yohei Kawabata ; Kazuhiro Yamashita ; Koichi Wada ; Yukinori Yamauchi ; Shizuo Yamada ; Satomi Onoue
• 关键词：ANOVA ; analysis of variance ; API ; active pharmaceutical ingredient ; AA ; adipic acid ; D ; l-aspartic acid ; AUC ; area under the curve of plasma concentration vs. time ; BCS ; biopharmaceutics classification system ; CA ; citric acid monohydrate ; Cmax ; maximum co
• 刊名：International Journal of Pharmaceutics
• 出版年：2012
• 出版时间：15 September, 2012
• 年：2012
• 卷：434
• 期：1-2
• 页码：148-154
• 全文大小：575 K

文摘

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 (10 mg 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 3 h (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.