不同工艺制备BCSⅡ类药物固体分散体的性质

Study on the properties of felodipine solid dispersions prepared by different technologies

目的:制备生物药剂学分类系统Ⅱ(Biopharmaceutics Classification SystemⅡ,BCSⅡ)类药物非洛地平固体分散体,并比较各非洛地平固体分散体的性质。方法:主要通过喷雾干燥法、微波淬冷法、冷冻干燥法和共沉淀法制备非洛地平/共聚维酮固体分散体,利用扫描电子显微镜(scanning electron microscope,SEM)、差式扫描量热(differential scanning calorimetry,DSC)和粉末X射线(X-ray diffraction,XRD)对所得固体分散体进行内在无定型性质分析,通过溶出实验来研究各工艺所得非洛地平固体分散体改善药物难溶性质的特征,通过超饱和实验研究聚合物对超饱和药物的结晶抑制效应。结果:喷雾干燥法、微波淬冷法及共沉淀法所得固体分散体内部药物以无定型形式存在,冷冻干燥法所得固体分散体内部药物以微晶形式存在。微波淬冷法比其他方法更能显著地改善难溶性药物非洛地平的溶出(P<0.05),60 min后溶出达到4.65 mg/L。共聚维酮能延缓或抑制超饱和非洛地平的结晶,在预溶最大量共聚维酮的溶液中,超饱和非洛地平在240 min时的结晶速率最小,为0.19 mg/(L·min)。结论:阐明了不同工艺所制得固体分散体的内在性质,为难溶性药物固体分散体的实际生产工艺选择提供参考。

Objective： To prepare felodipine / copovidone solid dispersions,which were made based on different preparation technologies. Insoluble felodipine was selected as the model drug in this research.This drug belonged to Biopharmaceutics Classification System Ⅱ（ BCS Ⅱ） with insoluble property and good permeability across intestinal mucosa simultaneously. A comparative study was carried out for further investigating their corresponding pharmaceutical properties. Methods： Felodipine / copovidone solid dispersions were achieved by four methods including spray-drying method,microwave-induced fusion quench cooling method,freeze-drying method and co-precipitation method. These solid dispersions were produced based on corresponding processes that corresponded to these methods. Internal properties of copovidone solid dispersions were analyzed by various approaches including scanning electron microscope（ SEM）,differential scanning calorimetry（ DSC） and powder X-ray diffraction（ PXRD）. The improvement on insoluble properties of felodipine by solid dispersions produced by different technologies was characterized by dissolution experiments based on dissolution instrument. Crystallization inhibition effect of polymers against drugs was studied by supersaturated experiments through determining the concentration value at different time points. Results： The internal drug was dispersed in amorphous form in solid dispersions produced by spray-drying,microwave method,microwave / quench-cooling method and coprecipitation method. Freeze-drying method resulted in a form of crystal in felodipine / copovidone solid dispersions. Compared with other technologies,microwave-induced quench cooling method could significantly improve the dissolution of insoluble drug felodipine（ P〈0. 05）. The dissolution concentration reached approximately 4. 65 mg / L at 60 min time point. Copovidone could inhibit or retard the crystallization of felodipine in a supersaturated state. In the solution pre-dissolved with maximum copoyidone polymer,the minimum crystallization rate of supersaturated felodipine was observed at 240 min time point.The value of crystallization rate was 0. 19 mg /（ L · min）. Conclusion： The study is helpful to understand and clarify the internal properties of solid dispersions obtained by different technologies. The research also provides beneficial consultation for the choice of technology in practical production of drugpolymer solid dispersions.