金丝桃苷混合纳米胶束的制备及其肠吸收研究  

Study on the preparation of hyperoside mixed nanomicelles and its intestinal absorption

作　　者：张宇航 邱智东[1] 邱野[1] 王伟楠[1] 刁元元 石羽文 姜孟成 刘伟朋 贾艾玲[1] ZHANG Yuhang;QIU Zhidong;QIU Ye;WANG Weinan;DIAO Yuanyuan;SHI Yuwen;JIANG Mengcheng;LIU Weipeng;JIA Ailing(Key Laboratory of Traditional Chinese Medicine Active Ingredient of Ministry of Education,Changchun University of Chinese Medicine,Changchun 130117,China)

机构地区：[1]长春中医药大学中药有效成分省部共建教育部重点实验室,长春130117

出　　处：《中国药房》2022年第10期1189-1197,共9页China Pharmacy

基　　金：吉林省科技发展计划项目(No.20210204004YY,No.20200602034ZP);长春中医药大学“杏林学者工程”——青年科学家项目(No.QNKXJ2-2021ZR26)。

摘　　要：目的制备金丝桃苷混合纳米胶束(Hyp-F127/TPGS)并优化其制备工艺,考察其肠吸收特性。方法采用薄膜分散法制备Hyp-F127/TPGS。在单因素实验和Plackett-Burman实验设计的基础上,结合Box-Behnken响应面法,以包封率和载药量为考察指标,以F127-TPGS质量比、水化时间、Hyp投药量为因素,优化其制备工艺并验证;观察按最优工艺所制Hyp-F127/TPGS的外观、微观形态并测定其粒径、多分散性指数(PDI)和Zeta电位;考察空白胶束(F127/TPGS)的临界胶束浓度(CMC)、Hyp-F127/TPGS的体外释放行为和初步稳定性,利用大鼠在体单向肠灌流模型评价Hyp-F127/TPGS肠吸收特性。结果Hyp-F127/TPGS的最优制备工艺为:F127-TPGS质量比2∶1、水化时间2 h、Hyp投药量9 mg;3次验证实验结果显示,所制Hyp-F127/TPGS的包封率为(87.20±0.99)%,载药量为(5.02±1.20)%,与预测值的偏差分别为0.92%和2.39%。按最优工艺所制胶束为黄色澄清透明溶液,具有良好的丁达尔效应;透射电子显微镜下呈球形,形态完整且分布均匀,粒径为(15.02±0.16)nm,PDI为0.092±0.031,Zeta电位为(-6.67±1.47)m V;F127/TPGS的CMC为21μg/mL,Hyp-F127/TPGS在4℃下存放4周的稳定性良好;Hyp-F127/TPGS和Hyp对照品的累积释放率分别为(66.30±2.93)%(96 h)、(99.24±0.27)%(60 h);Hyp-F127/TPGS和Hyp对照品在各肠段均有吸收,主要吸收部位分别为空肠和十二指肠,前者的药物吸收速率常数和表观吸收系数均显著高于后者(P<0.05或P<0.01)。结论优化所得Hyp-F127/TPGS制备工艺稳定、可行;所制Hyp-F127/TPGS具有缓释效果,并在一定程度上促进了Hyp的肠吸收。OBJECTIVE To prepare hyperoside mixed nanomicelles(Hyp-F127/TPGS)and optimize its preparation technology,and to investigate its intestinal absorption characteristics.METHODS Hyp-F127/TPGS was prepared by thin film dispersion method.Based on single factor test and Plackett-Burman design,combined with Box-Behnken response surface method,the preparation process was optimized and validated using entrapped efficiency(EE)and drug loading(DL)as evaluation indexes,F127-TPGS mass ratio,hydration time and the amount of Hyp as factors.The appearance and microscopic morphology of HypF127/TPGS obtained by the optimal technology were observed,and the particle size,polydispersity index(PDI)and Zeta potential were also determined.The critical micelle concentration(CMC)of blank micelle(F127/TPGS),in vitro release behavior and preliminary stability of Hyp-F127/TPGS were investigated,and absorption characteristics of Hyp-F127/TPGS were investigated by in situ unidirectional intestinal perfusion model.RESULTS The optimal preparation technology of Hyp-F127/TPGS included F127-TPGS mass ratio of 2∶1,hydration time of 2 h,and Hyp amount of 9 mg.Results of three validation tests showed that the EE of Hyp-F127/TPGS was(87.20±0.99)%,and the DL was(5.02±1.20)%,deviations from predicted values were 0.92%and2.39%.The micelles prepared by optimal technology were yellow,clear and transparent solution,with good Tyndall effect;under transmission electron microscope,they were spherical,complete and evenly distributed;the particle size was(15.02±0.16)nm,the PDI was 0.092±0.031,and the Zeta potential was(-6.67±1.47)mV.The CMC of F127/TPGS was 21μg/mL,Hyp-F127/TPGS was stable after 4 weeks of storage at 4℃,and the cumulative release rates of Hyp-F127/TPGS and Hyp control were(66.30±2.93)%(96 h)and(99.24±0.27)%(60 h),respectively.Hyp-F127/TPGS and Hyp reference were absorbed in each intestinal segment,and the main absorption sites were jejunum and duodenum respectively;drug absorption rate constant and apparent absorption coefficient of th

关 键 词：金丝桃苷 混合纳米胶束 制备工艺 肠吸收特性 PLACKETT-BURMAN设计 Box-Behnken响应面法 单向肠灌流模型 

分 类 号：R943[医药卫生—药剂学]