Hot melt extrusion technology for improved dissolution, solubility and 'spring-parachute' processes of amorphous self-micellizing solid dispersions containing BCS II drugs indomethacin and fenofibrate: Profiles and mechanisms

摘要

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 selfmicellizing Soluplus (R) 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, selfmicellizing Soluplus (R) 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 HME . 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.