目的 以莱鲍迪苷A为载体制备薯蓣皂苷元自组装胶束（diosgenin-rebaudioside A self-assembled nanomicelles，Dio-Reb A-SNM），考察体内口服药动学及降血糖作用。方法 单因素实验考察Dio-Reb A-SNM处方工艺。选择莱鲍迪苷A与薯蓣皂苷元用量比、薯蓣皂苷元质量浓度和超声时间为主要影响因素，包封率和载药量的总评归一值为优化指标，采用Box-Behnken设计-效应面法（Box-Behnken design-response surface method，BBD-RSM）优化Dio-Reb A-SNM处方工艺。透射电子显微镜（transmission electron microscope，TEM）观察Dio-Reb A-SNM微观形态，X-射线粉末衍射法（X-ray powder diffraction，XRPD）分析薯蓣皂苷元在Dio-Reb A-SNM粉末中的晶型。考察Dio-Reb A-SNM在不同pH值介质中的饱和溶解度及体外释药行为。SD大鼠分别ig给予薯蓣皂苷元和Dio-Reb A-SNM，测定血药浓度，计算Dio-Reb A-SNM相对生物利用度。构建大鼠2型糖尿病（type 2 diabetes mellitus，T2DM）模型，比较薯蓣皂苷元和Dio-Reb A-SNM对T2DM大鼠血糖、血清天冬氨酸氨基转移酶（aspartate aminotransferase，AST）、丙氨酸氨基转移酶（alanine aminotransferase，ALT）、尿素氮和肌酸酐水平的影响。HE染色法观察大鼠肝、肾病理情况。结果 Dio-Reb A-SNM最佳处方：莱鲍迪苷A与薯蓣皂苷元用量比为12.32∶1，薯蓣皂苷元质量浓度为1.97 mg/mL，超声时间为20.20 min。Dio-Reb A-SNM的包封率、载药量、粒径及ζ电位分别为（93.59±0.63）%和（5.65±0.07）%、（25.66±1.76）nm和（-24.59±1.18）mV。Dio-Reb A-SNM外貌为类球形，薯蓣皂苷元在Dio-Reb A-SNM粉末中转变为无定形态。Dio-Reb A-SNM极大提高了薯蓣皂苷元在不同pH介质中的饱和溶解度。Dio-Reb A-SNM体外释药具有缓释特征，18 h内累积释放度提高至90.94%，释药过程符合Weibull模型。药动学结果显示，Dio-Reb A-SNM的达峰时间（t_max）提前至（2.06±0.29）h，半衰期（t_1/2）延长至（8.39±1.94）h，达峰浓度（C_max）和相对生物利用度分别增加至3.59倍和6.82倍。与薯蓣皂苷元（30 mg/kg）相比，Dio-Reb A-SNM（30 mg/kg）可使T2DM大鼠第4周血糖极显著下降（P＜0.01），血清中AST、ALT、尿素氮、肌酸酐水平均极显著降低（P＜0.01），且肝、肾病理损伤进一步减轻。结论 Dio-Reb A-SNM显著促进了薯蓣皂苷元口服吸收，并提高了体内降血糖药效。

Objective To prepare diosgenin-rebaudioside A self-assembled nanomicelles (Dio-Reb A-SNM), and evaluate its oral pharmacokinetics and hypoglycemic effects in vivo. Methods Single factor experiment was employed to investigate the prescriptions of Dio-Reb A-SNM. The amounts ratio of rebaudioside A to diosgenin, diosgenin concentration and ultrasonic time were selected as main influencing factor, the overall desirability of envelopment efficiency and drug loading was employed as optimization index, and Box-Behnken response surface design method (BBD-RSM) was employed to optimize prescriptions of Dio-Reb A-SNM. Transmission electron microscope (TEM) was employed to observe the microscopic appearance of Dio-Reb A-SNM, and X-ray powder diffraction (XRPD) was employed to analyze the crystal form of diosgenin in Dio-Reb A-SNM powder. The saturated solubility and release behavior of Dio-Reb A-SNM were determined in different pH media. SD rats were administered intragastrically with diosgenin and Dio-Reb A-SNM, respectively. Blood drug concentration was determined, and the relative oral bioavailability of Dio-Reb A-SNM was calculated. The model of type 2 diabetes mellitus (T2DM) in rats was established, and the effects of diosgenin and Dio-Reb A-SNM on hypoglycemic effects, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea nitrogen and creatinine level were compared. The histopathological state of liver and kidney was observed by HE staining method. Results The optimal formulations of Dio-Reb A-SNM: amounts ratio of rebaudioside A to diosgenin was 12.32:1, diosgenin concentration was 1.97 mg/mL and ultrasonic time was 20.20 min. Envelopment efficiency, drug loading, particle size and ζ potential were (93.59 ±0.63)%, (5.65 ±0.07)%, (25.66 ±1.76) nm and (−24.59 ±1.18) mV, respectively. The appearance of Dio-Reb A-SNM were spherical. The crystal form of diosgenin changed into an amorphous form in Dio-Reb A-SNM powder. Dio-Reb A-SNM greatly improved the saturated solubility of diosgenin in different pH media. Drug release behavior of Dio-Reb A-SNM in vitro had obvious sustained-release characteristics, the cumulative release rate was increased to 90.94% in 18 h, and the drug release process conformed to Weibull model. Pharmacokinetics showed that t_max of Dio-Reb A-SNM was shortened to (2.06 ±0.29) h, t_1/2 was increased to (8.39 ±1.94) h, C_max and oral relative bioavailability were increased to 3.59-fold and 6.82-fold, respectively. Compared with diosgenin group (30 mg/kg), Dio-Reb A-SNM (30 mg/kg) could significantly reduce the blood glucose of T2DM rats at the fourth week (P < 0.01), and effectively reduced the AST, ALT, urea nitrogen and creatinine level in serum (P < 0.01). The pathological damage of liver and kidney was further alleviated by Dio-Reb A-SNM. Conclusion Dio-Reb A-SNM significantly promoted the oral absorption of diosgenin and improved hypoglycemic efficacy in vivo.

R283.6

河南省科技厅软科学研究项目（252400410062）；河南省高等学校重点科研项目计划（23B310010）