School of Pharmacy, University of Otago, Dunedin, New Zealand.
Eur J Pharm Biopharm. 2012 May;81(1):159-69. doi: 10.1016/j.ejpb.2012.02.004. Epub 2012 Feb 14.
The objective of this study was to prepare a co-amorphous drug/drug combination between two BCS class II drugs, simvastatin (SVS) and glipizide (GPZ). This pharmacologically relevant combination of two drugs could produce a promising candidate for formulations intended for combination therapy of metabolic disorders. The co-amorphous SVS-GPZ mixtures (molar ratios 2:1, 1:1 and 1:2) were prepared by mechanical activation (ball milling or cryomilling) and characterized with respect to their thermal properties, possible molecular interactions, dissolution properties and physical stability, and compared to the behaviour of pure amorphous forms and their physical mixtures. It was found that even though a molecular mixture was achieved with all SVS-GPZ mixture ratios, no molecular interactions between the drugs could be detected. By formation of co-amorphous single-phase mixtures, only the dissolution rate of GPZ could be improved. The co-amorphous mixtures showed improved stability compared to the pure amorphous forms and the amorphous physical mixtures. It was concluded that this was attributable to the molecular level mixing of SVS with GPZ upon milling, and GPZ is acting as an anti-plasticizer in these mixtures.
本研究的目的是制备两种 BCS 类 II 药物辛伐他汀（SVS）和格列吡嗪（GPZ）的共无定形药物/药物组合。这种具有药理学相关性的两种药物组合可能为旨在治疗代谢紊乱的联合治疗的制剂提供有前景的候选药物。通过机械活化（球磨或冷冻研磨）制备共无定形 SVS-GPZ 混合物（摩尔比为 2:1、1:1 和 1:2），并对其热性质、可能的分子相互作用、溶解性质和物理稳定性进行了表征，然后与纯无定形形式及其物理混合物的行为进行了比较。结果发现，尽管所有 SVS-GPZ 混合物比例都实现了分子混合物，但无法检测到药物之间的分子相互作用。通过形成共无定形单相混合物，只能提高 GPZ 的溶解速率。与纯无定形形式和无定形物理混合物相比，共无定形混合物显示出更好的稳定性。结论是，这归因于研磨过程中 SVS 与 GPZ 的分子水平混合，并且 GPZ 在这些混合物中充当抗塑化剂。
