Institute of Pharmaceutical Technology, Goethe University, Frankfurt, Germany.
Eur J Pharm Biopharm. 2013 May;84(1):208-18. doi: 10.1016/j.ejpb.2012.11.027. Epub 2012 Dec 13.
Low aqueous solubility is often a limiting aspect to the bioavailability of poorly soluble, but highly permeable drugs (class II compounds according to the Biopharmaceutics Classification System - BCS) administered in single drug products or as fixed dose combinations. The aim of the present series of experiments was to improve the solubility and dissolution of two fixed dose combination formulations (FDC), each consisting of two BCS class II drugs. The first FDC contained a weak acid (glimepiride) and a weak base (pioglitazone), while the second FDC contained two compounds (simvastatin and ezetimibe) that are essentially non-ionised over the physiological pH range. The formulation approaches used were as follows: (a) an inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD), (b) a solid dispersion with Soluplus, a new highly water soluble polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer and (c) a ternary inclusion complex with both HP-β-CD and Soluplus. Solid state analysis was performed for the pure drugs, and all formulations using powder X-ray diffraction (PXRD). The in vitro performance of the different formulation approaches, as gauged by solubility and dissolution experiments, was compared with that of the marketed products containing the respective fixed dose combinations, Tandemact 30 mg/4 mg tablets and Inegy 10 mg/40 mg tablets. The FDCs of the pure drugs and the marketed products showed very poor (and especially for pioglitazone, strongly pH-dependent) dissolution. By contrast, all binary and ternary inclusion complexes showed enhanced release for both drugs in the FDC. The ternary inclusion complex generated synergistic improvement in solubility and dissolution results for both FDCs. For example, in pH conditions of the fasted small intestine after a test duration of 240 min, we observed 100% dissolution of both drugs from the ternary pioglitazone/glimepiride (30 mg/4 mg) complex formulation, whereas from the marketed formulation less than 5% pioglitazone, and only 25% glimepiride dissolved. Using the same conditions, 60% ezetimibe and 85% simvastatin dissolved from the ternary ezetimibe/simvastatin (10 mg/40 mg) complex formulation, whereas with less than 5% ezetimibe and 10% simvastatin dissolved after 240 min, the marketed FDC formulation showed poor dissolution. Based on the results of the present study, the bioavailability of both drugs in the fixed dose combination is likely to be increased after oral administration of the new formulations, especially when the fixed dose combination is formulated as a ternary complex consisting of HP-β-CD and Soluplus.
低水溶性通常是生物利用度的限制因素，对于水溶性差但渗透性高的药物（根据生物药剂学分类系统 - BCS 为 II 类化合物），无论是单一药物产品还是固定剂量复方制剂给药都会存在这种情况。本系列实验的目的是提高两种固定剂量复方制剂（FDC）的溶解度和溶解速率，每个制剂都由两种 BCS II 类药物组成。第一个 FDC 包含一种弱酸（格列美脲）和一种弱碱（吡格列酮），而第二个 FDC 包含两种基本上在生理 pH 范围内非离子化的化合物（辛伐他汀和依折麦布）。所采用的制剂方法如下：（a）与羟丙基-β-环糊精（HP-β-CD）形成包合物，（b）与 Soluplus 形成固体分散体，Soluplus 是一种新型高水溶性聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物，（c）与 HP-β-CD 和 Soluplus 形成三元包合物。使用粉末 X 射线衍射（PXRD）对纯药物和所有制剂进行了固态分析。通过溶解度和溶解实验来比较不同制剂方法的体外性能，并与含有相应固定剂量复方的市售产品进行比较，即 Tandemact 30 mg/4 mg 片剂和 Inegy 10 mg/40 mg 片剂。纯药物的 FDC 和市售产品的 FDC 显示出非常差的（尤其是对于吡格列酮，强烈依赖 pH）溶解。相比之下，所有二元和三元包合物均显示出 FDC 中两种药物的释放增强。三元包合物对两种 FDC 的溶解度和溶解结果均产生协同改善。例如，在测试持续 240 分钟后，在空腹状态下的小肠快速转运条件下，我们观察到三元吡格列酮/格列美脲（30 mg/4 mg）复合物制剂中两种药物的 100%溶解，而市售制剂中吡格列酮的溶解不到 5%，仅 25%的格列美脲溶解。使用相同条件，三元依折麦布/辛伐他汀（10 mg/40 mg）复合物制剂中 60%的依折麦布和 85%的辛伐他汀溶解，而在 240 分钟后，市售 FDC 制剂中不到 5%的依折麦布和 10%的辛伐他汀溶解。根据本研究的结果，口服新制剂后，两种药物在固定剂量复方中的生物利用度可能会提高，特别是当固定剂量复方制剂作为由 HP-β-CD 和 Soluplus 组成的三元复合物进行配制时。
