Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Int J Pharm. 2012 Apr 15;426(1-2):61-66. doi: 10.1016/j.ijpharm.2012.01.014. Epub 2012 Jan 14.
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.
本研究旨在开发和表征双嘧达莫（DP）的新制剂，DP 是一种依赖 pH 值的难溶性药物，采用酸性 pH 值调节剂来改善低胃酸条件下的溶解和吸收。采用湿法制粒制备了含有富马酸（FA）和不含 FA 的 DP 颗粒剂（DPG），并对其理化性质进行了特征描述，重点关注形态、溶解和稳定性。将 DPG 或载有 60%FA 的 DPG（DPG/FA60）经口给药后，在奥美拉唑治疗的大鼠中进行药代动力学研究，作为低胃酸模型。虽然 DPG 表现出 pH 依赖性溶解行为，但 DPG/FA 在酸性和中性介质中均表现出高溶解速率和高溶解程度。在 pH6.8 介质中 2 小时测试期内实现完全超饱和，共存的富马酸对固体状态下 DP 的化学/光化学稳定性没有影响。与正常大鼠相比，奥美拉唑治疗的大鼠口服 DPG 或 DPG/FA60（10mg-DP/kg）后，DPG 的 AUC(0-3)减少约 40%；然而，低胃酸条件下 DPG/FA60 的 AUC(0-3)与正常大鼠中 DPG 的 AUC(0-3)几乎相同。鉴于在低胃酸大鼠中口服给药后早期系统暴露得到改善，DPG/FA 可能为低胃酸患者提供更好的临床疗效。
