Li Yongjun, Mann Amanda K P, Zhang Dan, Yang Zhen
Department of Pharmaceutical Sciences, MRL, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Pharmaceutics. 2021 Aug 21;13(8):1307. doi: 10.3390/pharmaceutics13081307.
Presently, a large number of drug molecules in development are BCS class II or IV compounds with poor aqueous solubility. Various novel solubilization techniques have been used to enhance drug solubility. Among them, amorphous solid dispersions (ASD), which convert a crystalline drug into an amorphous mixture of drug and polymer, have been demonstrated to be an effective tool in enhancing drug solubility and bioavailability. There are multiple ways to produce amorphous solid dispersions. The goal of the present study is to investigate two commonly used processing methods, hot-melt extrusion (HME) and spray drying, and their impact on drug bioperformance. The amorphous solid dispersions of a model compound, posaconazole (25% drug loading) in HPMCAS-MF, were successfully manufactured via the two processing routes, and the physicochemical properties, in vitro and in vivo performance of the resulting ASDs were characterized and compared. It was found that in vitro drug release of the ASDs from two-stage dissolution was significantly different. However, the two ASDs showed similar in vivo performance based on cynomolgus monkey PK studies. A mechanistic understanding of the in vitro and in vivo behaviors of the solid dispersions was discussed.
目前，大量处于研发阶段的药物分子属于生物药剂学分类系统（BCS）中的II类或IV类化合物，其水溶性较差。人们已采用各种新型增溶技术来提高药物溶解度。其中，无定形固体分散体（ASD）可将结晶药物转化为药物与聚合物的无定形混合物，已被证明是提高药物溶解度和生物利用度的有效工具。制备无定形固体分散体有多种方法。本研究的目的是考察两种常用的制备方法，即热熔挤出（HME）和喷雾干燥，以及它们对药物生物学性能的影响。通过这两种制备工艺成功制备了模型化合物泊沙康唑（载药量25%）在羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS-MF）中的无定形固体分散体，并对所得无定形固体分散体的理化性质、体外和体内性能进行了表征和比较。结果发现，两种无定形固体分散体在两阶段溶出中的体外药物释放存在显著差异。然而，基于食蟹猴的药代动力学（PK）研究，这两种无定形固体分散体显示出相似的体内性能。本文还讨论了对固体分散体体外和体内行为的机理理解。
