目的 研究双氢青蒿素（dihydroartemisinin，DHA）自微乳给药系统（self-microemulsion drug delivery system，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）mV，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.

R283.6

国家重大科技专项（2017ZX09101002-001-005）