Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Int J Pharm. 2012 Sep 15;434(1-2):148-54. doi: 10.1016/j.ijpharm.2012.05.040. Epub 2012 May 27.
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.
本研究旨在开发新的双嘧达莫（DP）制剂，用酸性微环境 pH 调节剂来改善低胃酸条件下的溶解和吸收。用常规湿法制粒法制备了十种酸性 pH 调节剂的双嘧达莫颗粒（DPG），并对其可制造性、稳定性和溶解行为进行了表征。在奥美拉唑治疗的大鼠低胃酸模型中，对优化后的含酸 DPG 进行了药代动力学分析。基于新 DPG 制剂的可制造性、稳定性和溶解行为，发现对甲苯磺酸（TS）是 DPG 制剂合适的酸性 pH 调节剂。虽然 DPG 表现出 pH 依赖性溶解行为，但 DPG 与 TS 在酸性和中性介质中均表现出高溶解速率和程度。在奥美拉唑治疗的低胃酸大鼠中口服给予 DPG（10mg DP/kg）后，与正常大鼠相比，DPG 的血浆浓度-时间曲线下面积（AUC（0-3））从 0 到 3 小时（AUC（0-3））降低了约 40%。然而，DPG/TS 在低胃酸条件下的 AUC（0-3）几乎与正常大鼠中 DPG 的 AUC（0-3）相同。从这些发现中可以看出，在 DP 制剂中添加 TS 作为微环境 pH 调节剂可能有助于扩大 DP 在低胃酸患者中的治疗潜力。
