热熔挤出技术制备泊沙康唑固体分散体及其体外评价

Preparation of posaconazole solid dispersion via hot-melt extrusion and preliminary evaluation in vitro

采用热熔挤出(HME)技术制备难溶性药物泊沙康唑(POS)固体分散体,提高其溶出度。利用溶解度参数、玻璃化转变温度和熔融法,初步筛选载体。进一步运用HME技术制备POS固体分散体,以溶出度为指标考察载体Kollidon VA64、Soluplus、Eudragit L100以及混合载体Kollidon VA64-Eudragit L100对药物的增溶能力。考察影响固体分散体溶出度的处方以及工艺因素、不同载体、挤出温度、增塑剂和载药量对溶出度的影响。采用差示扫描量热法(DSC)进行物相分析,并通过影响因素实验初步分析固体分散体的稳定性。结果显示以Kollindon VA64-Eudragit L100(2∶8)为载体,10%柠檬酸三乙酯为增塑剂,150℃挤出温度下制备的POS固体分散体,显著提高了POS的溶出度,DSC结果显示药物以无定形或分子形式存在于载体中。混合载体的比例、挤出温度、载药量以及增塑剂均能影响药物的溶出。固体分散体对湿度敏感,高温和强光条件下稳定。采用HME技术制备的固体分散体可以显著提高POS的溶出度。

Hot-melt extrusion technology was used to prepare solid dispersion of posaconazole for improving its dissolution. Solubility parameter, glass transition temperature and melting method were utilized to screen poly- mers. Using KollidonVA64, Soluplus, Eudragit L100 and combined carrier KollidonVA64-Eudragit L100 as poly- mer carrier, solid dispersion was prepared by hot-melt extrusion technology and characterized by drug dissolu- tion. The formulation and process factor affecting dissolution were studied. The state of posaconazole in solid dis- persion was characterized by differential scanning calorimetry and preliminary analysis of the stability was studied by influencing factors experiments. When using KollidonVA64-Eudragit L100 （2 ： 8） as the carrier, 10 % triethyl citrate as the plasticizer and extrusion temperature of 150 ~C, the dissolution of posaconazole was improved signif- icantly. Drug was molecular or amorphous form in the carrier. Proportion of Eudragit L100 and KollidonVA64, temperature, drug loading and plasticizer influenced dissolution of posaconazole. Solid dispersion was stable for high temperature and strong light but sensitive to high humidity. Solid dispersion using hot-melt extrusion technol- ogy can significantly improve the dissolution of posaconazole.