目的 制备甜菊素-隐丹参酮自胶束化固体分散体（steviosin-cryptotanshinone self-micelle solid dispersion，Ste/Cry-SMSD），考察其口服生物利用度和降血糖作用。方法 采用Ste/Cry-SMSD自组装胶束的包封率和载药量为考察指标，使用Box-Behnken设计-响应面法（Box-Behnken design-response surface method，BBD-RSM）优化Ste/Cry-SMSD处方工艺。X射线粉末衍射（X-ray powder diffraction，XRPD）法分析隐丹参酮在Ste/Cry-SMSD粉末中的晶型，傅里叶变换红外光谱（Fourier transform infrared spectroscopy，FT-IR）研究结合机制，透射电子显微镜（transmission electron microscope，TEM）观察Ste/Cry-SMSD自组装胶束的微观形貌，透析袋法考察Ste/Cry-SMSD在模拟胃、肠液中释药情况。以隐丹参酮原料药为参考，考察Ste/Cry-SMSD相对口服生物利用度。建立大鼠糖尿病模型，以隐丹参酮原料药为参考，评价Ste/Cry-SMSD降血糖药效和口服糖耐量。结果 Ste/Cry-SMSD最佳处方：甜菊素质量浓度为2.70 mg/mL，制备温度为52.0 ℃，搅拌时间为60.00 min。Ste/Cry-SMSD自组装形成胶束的包封率为（94.77±0.57）%，载药量为（8.11±0.06）%，粒径为（8.69±0.56）nm，ζ电位为（−16.19±0.92）mV。隐丹参酮和甜菊素可能以氢键结合在一起，并以无定型形式存在于Ste/Cry-SMSD粉末中，Ste/Cry-SMSD在模拟胃、肠液中释药行为符合Weibull模型。药动学结果显示，Ste/Cry-SMSD达峰浓度（C_max）为（1 129.34±206.13）ng/mL，半衰期（t_1/2）延长至（4.15±0.82）h，与隐丹参酮原料药相比相对口服吸收生物利用度提高至6.11倍。Ste/Cry-SMSD显著增强了隐丹参酮降血糖药效、血糖调节能力及口服糖耐量。结论 Ste/Cry-SMSD处方简单，显著增加了隐丹参酮生物利用度，并增强了其降血糖作用。

Objective To prepare steviosin-cryptotanshinone self-micelle solid dispersion (Ste/Cry-SMSD), and investigate oral bioavailability and hypoglycemic effects. Methods Encapsulation efficiency and drug loading of self-assembled micelles acted as evaluation indexes, the formulation of Ste/Cry-SMSD was optimized by Box-Behnken design-response surface method. Crystal form of cryptotanshinone in Ste/Cry-SMSD powder was analyzed by X-ray powder diffraction (XRPD), combining mechanism was studied by Fourier transform infrared spectroscopy (FT-IR), morphology of self-assembled micelles was observed by transmission electron microscopy (TEM) and drug release behaviors in simulated gastrointestinal fluid were also investigated by dialysis bag method. The relative oral bioavailability of Ste/Cry-SMSD was investigated in comparison with cryptotanshinone. Diabetic model was established, and the glucose-decreasing effects and oral glucose tolerance of Ste/Cry-SMSD were compared with those of cryptanshinone. Results Optimal formulation of Ste/Cry-SMSD: the steviosin concentration is 2.70 mg/mL, preparation temperature is 52.0 ℃, and stirring time is 60.00 min. Encapsulation efficiency, drug loading, particle size and ζ potential of self-assembled micelles were (94.77 ±0.57)%, (8.11 ±0.06)%, (8.69 ±0.56) nm and (−16.19 ±0.92) mV, respectively. Cryptotanshinone and steviosin might be hydrogen-bonded and existed in the amorphous form in Ste/Cry-SMS powders. Drug release behaviors of Ste/Cry-SMSD in simulated gastrointestinal fluid were conformed to Weibull model. Pharmacokinetic results showed that C_max of Ste/Cry-SMSD was increased to (1 129.34 ±206.13) ng/mL, t_1/2 was prolonged to (4.15 ±0.82) h. The relative bioavailability of Ste/Cry-SMSD was increased to 6.11-fold compared to cryptotanshinone. Ste/Cry-SMSD significantly enhanced glucose-decreasing effects, blood glucose regulation ability and oral glucose tolerance of cryptotanshinone. Conclusion Ste/Cry-SMSD prescription was simple, which significantly increased the relative oral bioavailability and enhanced the glucose-decreasing effects of cryptotanshinone.

R283.6

河南省高等学校重点科研项目（24B310010）；河南省医学教育研究项目（WJLX2024191）；教育部产学研合作协同育人项目（230802175007047）