目的 制备含功能性油的水飞蓟宾超饱和自纳米乳（SLB-S-SNEDDS），并对其进行表征及体外评价研究，以提高难溶性药物水飞蓟宾的生物利用度。方法 铁氢化钾还原力与1，1-二苯基-2-苦肼基（DPPH）自由基清除实验筛选功能性油脂；伪三元相图考察乳化剂乳化能力；测定粒径、多分散指数（PDI）、Zeta电位等考察混合油相比例与载药量；相容性与溶出度实验筛选促过饱和物质并考察其质量浓度；从外观、粒径分布、自乳化效率、形态学等方面表征SLB-S-SNEDDS，并进行溶出度、抗氧化能力、细胞毒性等体外评价。结果 所得SLB-S-SNEDDS处方为（1）小麦胚芽油/Capryol 90-Cremophor ELP-Transcutol HP与（2）沙棘籽油/Capryol 90-Cremophor ELP-Transcutol HP，1 g基质（包含0.043 g小麦胚芽油或沙棘籽油、0.387 g Capryol 90、0.380 g Cremophor ELP、0.190 g Transcutol HP），水飞蓟宾的添加量为各组分平衡溶解度之和的20%，Soluplus的添加量为上述总质量的0.1%。小麦胚芽油、沙棘籽油体系分别为淡黄色、亮黄色透明状均一液体，2种体系自乳化分散后均呈近球形白色扁平乳滴，粒径约为50 nm，乳化时间均为65 s。与药物原料及SLB-SNEDDS相比，SLB-S-SNEDDS中水飞蓟宾的累积溶出率8 h内均维持在85%~110%，表明该体系能够显著提高药物的溶出度。SLB-S-SNEDDS与铁氰化钾反应后的吸光度（A值0.452~0.782，0.488~0.765）以及DPPH自由基清除率（39.09%~96.02%，30.54%~89.20%）均高于相应质量浓度下水飞蓟宾原料的A值与清除率（0.411~0.760，22.89%~63.21%），表明2种处方体系均能提高水飞蓟宾的抗氧化能力。细胞毒性实验结果显示，在5、10 μmol/L药物浓度下，水飞蓟宾原料组、水飞蓟宾S-SNEDDS组及其相应的空白S-SNEDDS组细胞生存率均>90%，说明SLB-S-SNEDDS及其所用辅料对人克隆结肠腺癌细胞（Caco-2）毒性较小、安全性较好。结论 制备的含功能性油SLB-S-SNEDDS在提高水飞蓟宾累积溶出率的同时，增强了其抗氧化能力，为将超饱和自纳米乳（S-SNEDDS）用于改善难溶性药物水溶性及其生物活性提供有益参考。

Objective In order to improve the bioavailability of the insoluble drug silybin, silybin supersaturated self-nanoemulsifying drug delivery systems (SLB-S-SNEDDS) containing functional oil were prepared, its characterization and in vitro evaluation were also performed. Methods Functional oils were screened by performing potassium ferrohydride reduction and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiments. The pseudo-ternary phase diagram was drawn to investigate the emulsifying ability of emulsifier. The proportion of mixed oil phase and drug loading capacity were explored by analyzing particle size, polydispersity index (PDI), zeta potential, etc. The type and concentration of supersaturated substance in SLB-S-SNEDDS were obtained by conducting the compatibility and dissolution experiments. SLB-S-SNEDDS was characterized with appearance, particle size distribution, self-emulsification efficiency, and morphology, and its in vitro dissolution, antioxidant capacity, and cytotoxicity were also evaluated. Results The prescriptions of SLB-S-SNEDDS were as follows:(1) wheatgerm oil/Capryol 90-Cremophor ELP-Transcutol HP; (2) seabuckthorn seed oil/Capryol 90-Cremophor ELP-Transcutol HP. One g S-SNEDDS matrix contained 0.043 g of wheatgerm oil or sea-buckthorn seed oil, 0.387 g of Capryol 90, 0.380 g of Cremophor ELP, and 0.190 g of Transcutol HP. The adding amount of silybin in S-SNEDDS prescription was 20% of the sum of the equilibrium solubility of silybin in each component, and the adding amount of Soluplus was 0.1% of the total mass described above. The two obtained SLB-S-SNEDDS were transparent homogeneous liquid with light yellow (wheat germ oil) and bright yellow (seabuckthorn seed oil) color, respectively. After being dispersed, SLB-S-SNEDDS turned into subspherical white flat emulsion droplets with the particle size of about 50 nm, and the emulsification time was 65 s. Compared with raw materials and SLB-SNEDDS, the cumulative dissolution of silybin in SLB-S-SNEDDS was maintained between 85% and 110% within 8 h, indicating that the two systems can significantly improve the dissolution of silybin. The absorbance of SLB-S-SNEDDS after reaction with potassium ferricyanide (0.452-0.782, 0.488-0.765) and the DPPH free radical clearance of SLB-S-SNEDDS (39.09%-96.02%, 30.54%-89.20%) were all higher than those of raw silybin (0.411-0.760, 22.89%-63.21%), which suggested that the two systems can enhance the antioxidant capacity of silybin. Cytotoxicity test results showed that the cell survival rate in silybin raw material group, combination of silybin and S-SNEDDS group, and blank S-SNEDDS group were greater than 90% at 5 μmol/L and 10 μmol/L drug concentration, indicating that SLB-S-SNEDDS and its auxiliary materials were safe and less toxic to human cloned colorectal adenocarcinoma cell line (Caco-2). Conclusion The SLB-S-SNEDDS containing functional oil prepared in this paper can not only increase the cumulative dissolution of silybin, but also enhance its antioxidant capacity, which provides a useful reference for supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) to improve the water-solubility and bioactivity of insoluble drugs.

R283.6

上海市科委优秀学术带头人资助项目（19XD1423700）