鞣花酸自胶束化固体分散体制备及口服药动学行为研究  

Preparation and oral pharmacokinetic study of ellagic acid-loaded self-micelle solid dispersion

作　　者：张亚林[1] 郭志刚[1] 王丹凤[1] 黄涛[1] 崔锋 ZHANG Yalin;GUO Zhigang;WANG Danfeng;HUANG Tao;CUI Feng(Huanghe Science and Technology College,Zhengzhou 450063,China;Bozhou Hi-tech Innovation Pharmaceutical Industry Technology Research Institute Co.,Ltd.,Bozhou 236839,China)

机构地区：[1]黄河科技学院,河南郑州450063 [2]亳州高新科创医药产业技术研究院有限公司,安徽亳州236839

出　　处：《中草药》2024年第13期4350-4360,共11页Chinese Traditional and Herbal Drugs

基　　金：国家教育部产学合作协同育人项目(2206005410900332);亳州市重点研发计划(bzzc2021044);普通高等学校学科专业建设资助项目(2020162001);河南省一流本科专业(药学)(202007387)。

摘　　要：目的制备鞣花酸自胶束化固体分散体(ellagic acid-loaded self-micelle solid dispersion,EA-SMSD),考察体外释药情况及口服药动学行为。方法以EA-SMSD自组装形成胶束的包封率、载药量和沉降率为指标,Box-Behnken设计-效应面法优化EA-SMSD处方工艺。透射电子显微镜(TEM)观察自组装胶束的微观形貌,X射线粉末衍射法(XRPD)分析鞣花酸在EA-SMSD粉末中的晶型,透析袋法考察EA-SMSD在水及模拟胃、肠液中释药情况。以鞣花酸原料药为参考,比较EASMSD口服药动学行为。结果EA-SMSD最佳处方:Soluplus与鞣花酸用量比为7.8∶1,制备温度为50℃,制备时间为1.6 h。自组装形成胶束的包封率为(94.62±1.12)%,载药量为(10.57±0.24)%,沉降率为(2.19±0.09)%,粒径为(68.90±6.87)nm,ζ电位为(-13.11±1.02)m V。鞣花酸以无定型形式存在于EA-SMSD粉末中,EA-SMSD在水及模拟胃、肠液中释药行为符合Weibull模型,且储存稳定性高。药动学结果显示,EA-SMSD达峰时间(tmax)延后至(5.15±0.98)h,达峰浓度(Cmax)提高至4.03倍,相对口服吸收生物利用度提高至6.03倍。结论EA-SMSD制备工艺简单,可显著增加鞣花酸相对口服吸收生物利用度。Objective To prepare ellagic acid-loaded self-micelle solid dispersion(EA-SMSD),and study drug release in vitro and oral pharmacokinetic behaviors in vivo.Methods Encapsulation efficiency,drug loading and sedimentation rate of self-assembled micelles acted as evaluation indexes,formulation of EA-SMSD was optimized by Box-Behnken design-response surface method.Morphology of self-assembled micelles was observed by transmission electron microscopy(TEM),and crystal form of ellagic acid in EA-SMSD powder was analyzed by X-ray powder diffraction(XRPD).Drug release behaviors of ellagic acid from EA-SMSD in water and simulated gastrointestinal fluid were also investigated.Using ellagic acid as control,oral pharmacokinetic behavior of EA-SMSD was also compared.Results Optimal preparation of EA-SMSD:Soluplus to ellagic acid ratio was 7.8:1,preparation temperature was 50℃ and preparation time was 1.6 h.Encapsulation efficiency,drug loading,sedimentation rate,particle size and ζ potential of the self-assembled micelles were(94.62±1.12)%,(10.57±0.24)%,(2.19±0.09)%,(68.90±6.87)nm and(−13.11±1.02)mV,respectively.Ellagic acid existed as an amorphous form in EA-SMSD powder.Drug release behaviors of EA-SMSD in water and simulated gastrointestinal fluid were conformed to Weibull model,and the storage stability was high.Pharmacokinetic results showed that tmax of EA-SMSD was delayed to(5.15±0.98)h,Cmax was increased to 4.03 times,and its relative bioavailability was increased to 6.03 times.Conclusion The preparation process of EA-SMSD was simple,and EA-SMSD could significantly increase the relative oral bioavailability of ellagic acid.

关 键 词：鞣花酸 自组装胶束 Box-Behnken设计-效应面法 释药行为 药动学 生物利用度 

分 类 号：R283.6[医药卫生—中药学]