Improved dissolution and pharmacokinetic behavior of dipyridamole formulation with microenvironmental pH-modifier under hypochlorhydria

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• 作者：Satomi Onoue^a ; ^{onoue@u-shizuoka-ken.ac.jp} ; Ryo Inoue^a ; Chika Taniguchi^a ; ^b ; Yohei Kawabata^a ; ^b ; Kazuhiro Yamashita^b ; Koichi Wada^b ; Yukinori Yamauchi^c ; Shizuo Yamada^a
• 关键词：ANOVA ; analysis of variance ; AUC ; area under the curve of blood concentration vs. time ; BA ; bioavailability ; Cmax ; maximum concentration ; CV ; coefficient of variation ; DP ; dipyridamole ; DPG ; granule formulation of dipyridamole ; FA ; fumaric acid ; HCl ; hydr
• 刊名：International Journal of Pharmaceutics
• 出版年：2012
• 期刊代码：24_03785173
• 类别：pha
• 出版时间：15 April, 2012
• 卷：426
• 期：1-2
• 页码：61-66
• 文件大小：534 K

摘要

The present study aimed to develop and characterize new formulations of dipyridamole (DP), a pH-dependent poorly soluble drug, employing an acidic pH-modifier for improving dissolution and absorption under hypochlorhydric condition. Granule formulations of DP (DPG) with and without fumaric acid (FA) were prepared with wet granulation, physicochemical properties of which were characterized focusing on morphology, dissolution and stability. Pharmacokinetic profiling of orally dosed DPG or DPG with 60%loading of FA (DPG/FA60) was carried out in omeprazole-treated rats as a hypochlorhydric model. Although pH-dependent dissolution behavior was observed in DPG, DPG/FA exhibited high rate and extent of dissolution in both acidic and neutral media. Complete supersaturation was achieved with a 2 h testing period in pH6.8 medium, and co-existing fumaric acid had no impact on the chemical/photochemical stability of DP in solid-state. After oral administration of DPG or DPG/FA60 (10 mg-DP/kg), there was ca. 40%reduction of AUC_0-3 for DPG in omeprazole-treated rats as compared to that in normal rats; however, AUC_0-3 for DPG/FA60 under hypochlorhydria was almost identical to that of DPG in normal rats. Given the improved systemic exposure early after oral administration in hypochlorhydric rats, the DPG/FA might provide better clinical outcomes in hypochlorhydric patients.