薯蓣皂苷元无定形固体分散体制备及体内外评价  

Preparation and evaluation of diosgenin amorphous solid dispersion in vitro and in vivo

作　　者：刘沛[1] 常金花[1] 康凯 薛禾菲 王雨欣 徐林 刘翠哲[1] 周剑宇[1] LIU Pei;CHANG Jin-hua;KANG Kai;XUE He-fei;WANG Yu-xin;XU Lin;LIU Cui-zhe;ZHOU Jian-yu(Hebei Province Key Laboratory of Nerve Injury and Repair,Hebei Province Key Laboratory of Research and Development for Chinese Medicine,Chengde Medical College,Chengde 067000,China)

机构地区：[1]承德医学院河北省神经损伤与修复重点实验室,河北省中药研究与开发重点实验室,河北承德067000

出　　处：《中草药》2022年第14期4323-4332,共10页Chinese Traditional and Herbal Drugs

基　　金：河北省高等学校科学技术研究项目(QN2020241);河北省高等学校科学技术研究项目(QN2019167);河北省高校重点学科建设项目(冀教高[2013]4号);河北省科技厅“技术创新引导专项-科技工作会商”项目;河北省神经损伤与修复重点实验室开放课题(NJKF202102)。

摘　　要：目的制备薯蓣皂苷元无定形固体分散体(diosgenin amorphous solid dispersion,Dio-ASD),提高Dio溶出度和生物利用度。方法应用分子模拟技术分析Dio与载体之间相互作用并通过抑晶实验验证,构建Dio与载体混溶性曲线相图,理论预测二者混溶性;以Soluplus为载体,应用共沉淀法制备Dio-ASD;通过溶出度测定、差示扫描量热分析(differential scanning calorimetry,DSC)、X-射线粉末衍射(X-ray powder diffraction,XRPD)、扫描电镜分析(scanning electron microscopy,SEM)、傅里叶红外光谱(Fourier transform infrared spectroscopy,FT-IR)对Dio-ASD进行体外评价;采用UPLC-MS/MS方法测定大鼠体内Dio血药浓度,计算药动学参数,对Dio-ASD进行体内评价。结果分子模拟结果显示Soluplus与Dio之间能形成疏水键和氢键相互作用,结合能强于其他载体,且Soluplus对Dio的抑晶作用最强。构建了混溶性曲线相图,Dio与Soluplus在25℃下的混溶性为68.57%。与原料药相比,Dio-ASD溶出度明显提高。物相表征结果显示,Dio以无定形态存在于Dio-ASD中,Dio和Soluplus之间存在相互作用。药动学结果表明大鼠ig给药后,Dio-ASD的生物利用度较Dio提高了近5倍。结论制备的Dio-ASD可以显著提高药物溶出度和大鼠体内生物利用度。Objective To prepare diosgenin amorphous solid dispersion(Dio-ASD)and improve the dissolution and bioavailability of Dio.Methods The interaction between Dio and carrier was analyzed by molecular simulation technology and verified by crystal suppression experiment.The phase diagram of the miscibility curve between Dio and carrier was constructed,and the miscibility of Dio and carrier was predicted theoretically.Dio-ASD was prepared by coprecipitation with Soluplus as carrier and was evaluated in vitro by dissolution assay,differential scanning calorimetry(DSC),X-ray powder diffraction(XRPD),scanning electron microscopy(SEM),and fourier transform infrared spectroscopy(FT-IR).The plasma concentration of Dio in rats was determined by UPLC-MS/MS method,and the pharmacokinetic parameters were calculated to evaluate Dio-ASD in vivo.Results Molecular simulation results showed that hydrophobic and hydrogen interactions between Soluplus and Dio were formed,and the binding energy was stronger compared with other carriers.Soluplus had the strongest crystal suppression effect on Dio.The phase diagram of the miscibility curve was constructed and the miscibility between Dio and Soluplus at 25℃was 68.57%.Compared with the bulk drug,the dissolution rate of Dio-ASD was significantly improved.The phase characterization results showed that Dio existed in Dio-ASD in an amorphous state,and there was an interaction between Dio and Soluplus.The pharmacokinetics results showed that the bioavailability of Dio-ASD was nearly five times higher than that of Dio after intragastric administration to rats.Conclusion The prepared Dio-ASD can significantly improve drug dissolution and bioavailability in rats.

关 键 词：薯蓣皂苷元 无定形固体分散体 分子模拟 混溶性相图 药动学 

分 类 号：R283.6[医药卫生—中药学]