Kojo Yoshiki, Matsunaga Saori, Suzuki Hiroki, Taniguchi Chika, Kawabata Yohei, Wada Koichi, Yamauchi Yukinori, Seto Yoshiki, Sato Hideyuki, Onoue Satomi
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka.
Department of Chemistry, Manufacturing and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd.
Chem Pharm Bull (Tokyo). 2017;65(5):426-431. doi: 10.1248/cpb.c16-00714.
The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier.
本研究的目的是通过联合使用pH调节剂技术和采用肠溶聚合物Eudragit S100（Eud）的固体分散体（SD）技术，开发双嘧达莫（DP）的pH非依赖性释放制剂。酒石酸（TA）在改善DP在中性条件下的溶解行为方面被选为合适的pH调节剂。在优化TA与DP的比例后，通过冷冻干燥法制备了DP与Eud和TA的固体分散体（SD-Eud/DP/TA）。扫描电子显微镜图像显示，在SD-Eud/DP/TA中DP分散在聚合物中，粉末X射线衍射和差示扫描量热分析表明，SD-Eud/DP/TA中的DP处于无定形状态。SD-Eud/DP/TA的溶解行为不依赖于介质的pH值，尽管SD-Eud/DP在中性条件下的溶解行为非常有限。光谱分析表明，在SD-Eud/DP/TA中DP、TA和肠溶聚合物之间可能存在分子间相互作用，这可能导致SD-Eud/DP/TA具有稳定的pH非依赖性溶解行为。SD-Eud/DP/TA中的TA促进了DP的降解，这表明提高DP在SD-Eud/DP/TA中的稳定性可能是其实际应用的关键。从这些结果来看，通过基于肠溶聚合物的固体分散体与pH调节剂可以实现SD-Eud/DP/TA的pH非依赖性溶解行为。
