School of Pharmacy, Jilin Medical University, Jilin 132013, Jilin Province, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America; Biointerfaces Institute, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48109, United States of America.
School of Public Health, Jilin Medical University, Jilin 132013, Jilin Province, China.
Eur J Pharm Sci. 2019 Mar 15;130:78-90. doi: 10.1016/j.ejps.2019.01.019. Epub 2019 Jan 23.
Many strategies have been employed to improve oral drug delivery. One such approach involves the use of supersaturable delivery systems such as amorphous self-micellizing solid dispersions (SmSDs). SmSDs have attracted more attention recently, but little is known regarding the impact of production methods on profiles and internal mechanisms of final SmSDs in spite of its importance. In this study, amorphous SmSDs containing self-micellizing Soluplus® and BCS II drug (either indomethacin (IND) or fenofibrate (FEN)) were generated using various methods: solvent evaporation (SOL), freeze-drying (FD), microwave radiation-quench cooling (MQC), and hot melt extrusion (HME). Microscopic morphology, amorphous state, thermal behavior, dissolution/solubility, and "spring-parachute" data were used to assemble physicochemical profiles for SmSD systems prepared using each method. Analysis of intermolecular interactions, solubilization, and crystallization inhibition further uncovered internal mechanisms explaining observed physicochemical properties. Generally, SmSD/IND and SmSD/FEN systems generated using HME exhibited superior dissolution, solubility, and spring-parachute profiles. The superior advantages of HME-generated SmSD/IND systems were attributed to relatively stronger intermolecular interactions than observed in SmSD/IND systems fabricated using other methods. Moreover, self-micellizing Soluplus® carrier was able to solubilize IND or FEN and suppress drug crystallization from a supersaturated state, which seemed to be an important mechanism for the properties enhancement caused by SmSD/FEN. This knowledge should be useful for guiding further development of self-micellizing solid dispersions and for gaining deeper understanding of how HME technology can improve supersaturable drug delivery based on SmSDs strategy.
许多策略已被用于改善口服药物传递。一种这样的方法涉及使用超饱和递药系统，如无定形自胶束化固体分散体（SmSDs）。SmSDs 最近引起了更多的关注，但尽管其重要性，对于生产方法对最终 SmSDs 形态和内部机制的影响却知之甚少。在这项研究中，使用各种方法生成了含有自胶束化 Soluplus®和 BCS II 药物（吲哚美辛（IND）或非诺贝特（FEN））的无定形 SmSD：溶剂蒸发（SOL）、冷冻干燥（FD）、微波辐射淬火冷却（MQC）和热熔挤出（HME）。使用微观形貌、无定形态、热行为、溶解/溶解度和“弹簧降落伞”数据来组装每种方法制备的 SmSD 系统的物理化学特征。对分子间相互作用、增溶和结晶抑制的分析进一步揭示了解释观察到的物理化学性质的内部机制。一般来说，使用 HME 生成的 SmSD/IND 和 SmSD/FEN 系统表现出优越的溶解、溶解度和弹簧降落伞特性。HME 生成的 SmSD/IND 系统的优越优势归因于与通过其他方法制备的 SmSD/IND 系统中观察到的相比相对更强的分子间相互作用。此外，自胶束化的 Soluplus®载体能够增溶 IND 或 FEN 并抑制药物从过饱和状态结晶，这似乎是 SmSD/FEN 引起的性质增强的重要机制。这些知识对于指导自胶束化固体分散体的进一步发展以及深入了解 HME 技术如何基于 SmSD 策略改善超饱和药物传递应该是有用的。
