摘要
目的研究双氢青蒿素(dihydroartemisinin,DHA)自微乳给药系统(self-microemulsiondrugdeliverysystem,SMEDDS)(DHA-SMEDDS)的处方与制备工艺,并对其进行评价。方法通过溶解度实验、油相与乳化剂和助乳化剂配伍实验及伪三元相图的绘制,筛选DHA-SMEDDS的处方组成;以平均粒径、载药量为评价指标,采用星点设计-效应面法优化处方,并对DHA-SMEDDS的理化性质、初步稳定性进行评价。考察DHA-SMEDDS在马丁达比犬肾上皮MDCK细胞模型中促渗机制。结果优化后的DHA-SMEDDS处方中油相为辛癸酸甘油酯(15%)、乳化剂为聚氧乙烯40蓖麻油(46.4%)、混合助乳化剂为无水乙醇(24.12%)和聚乙二醇400(14.48%)。所得自微乳外观均一透明,自乳化后平均粒径(24.55±0.18)nm,多分散性指数(PDI)为0.092±0.028,电位为(-3.16±0.14)m V,载药量为(9.64±0.01)mg/g,包封率为(99.67±0.10)%,乳化时间为(13.90±0.10)s。初步稳定性实验表明,DHA-SMEDDS应常温避光保存。DHA-SMEDDS可以打开细胞间的紧密连接蛋白,降低细胞膜电位,增加细胞通透性,增强Ca2+-ATP酶活性。结论DHA-SMEDDS制备工艺简单,外观良好,乳化效率高,有望提高DHA的口服生物利用度。
Objective To study the formulation and preparation technology of dihydroartemisinin self-microemulsion drug delivery system(DHA-SMEDDS)and evaluate it.Methods The formulation of DHA-SMEDDS was screened by solubility test,oil phase with emulsifier and co-emulsifier compatibility experiment and pseudo ternary phase diagram drawing.Taking the mean particle size and drug loading as evaluation indexes,the formulation was optimized by central composite design-response surface methodology,and the physicochemical properties and initial stability of DHA-SMEDDS were evaluated.The mechanism of promoting infiltration of DHA-SMEDDS in MDCK cell model was investigated.Results In the optimized DHA-SMEDDS formulation,the oil phase was caprylic capric triglycerride(15%),the emulsifier was polyoxyethylene 40 castor oil(46.4%),the mixed co-emulsifier was anhydrous ethanol(24.12%)and polyethylene glycol 400(14.48%).The prepared self-microemulsion had uniform and transparent appearance.The average particle size after self-emulsification was(24.55±0.18)nm,PDI was(0.092±0.028),potential was(-3.16±0.14)mV,the drug loading was(9.64±0.01)mg/g,the entrapment efficiency was(99.67±0.10)%,and emulsifying time was(13.90±0.10)s.Preliminary stability experiments showed that DHA-SMEDDS should be stored at low temperature and away from light.DHA-SMEDDS can open tight junction proteins between cells,decrease cell membrane potential,increase cell permeability,and enhance Ca2+-ATPase activity.Conclusion DHA-SMEDDS has the advantages of simple preparation process,good appearance and high emulsifying efficiency,which is expected to improve the oral bioavailability of DHA.
作者
张然
杨冰
廖茂梁
华洁
周钰通
周福军
张铁军
ZHANG Ran;YANG Bing;LIAO Mao-liang;HUA Jie;ZHOU Yu-tong;ZHOU Fu-jun;ZHANG Tie-jun(Tianjin Medical University,Tianjin 300070,China;Tianjin Institute of Phannaceutical Research,Tianjin 300462,China;Tianjin Key Laboratory of Quality Markers of Traditional Chinese Medicine,Tianjin 300462,China;State Key Laboratory of Drug Delivery and Pharmacokinetics,Tianjin 300462,China)
出处
《中草药》
CAS
CSCD
北大核心
2021年第5期1291-1302,共12页
Chinese Traditional and Herbal Drugs
基金
国家重大科技专项(2017ZX09101002-001-005)。
关键词
双氢青蒿素
自微乳给药系统
伪三元相图
星点设计-效应面法
质量评价
溶解度
促渗机制
生物利用度
dihydroartemisinin
self-microemulsion drug delivery system
pseudo ternary phase diagram
central composite design-response surface methodology
quality evaluation
solubility
infiltration promotion mechanism
bioavailability
作者简介
张然(1993-),女,硕士研究生,研究方向为制剂研究与开发,Tel:15512060506,E-mail:245871768@qq.com;通信作者:周福军,硕士生导师,研究员,主要从事新药及制剂研发工作。E-mail:zhoufj@tjipr.com;通信作者:张铁军,硕士生导师,研究员,主要从事中药新药、中药质量和中药大品种二次开发研究。E-mail:zhangtj@tjipr.com。
