目的 制備甜菊素-隱丹參酮自膠束化固體分散體（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自組裝膠束的包封率和載藥量為考察指標(biāo)，使用Box-Behnken設(shè)計(jì)-響應(yīng)面法（Box-Behnken design-response surface method，BBD-RSM）優(yōu)化Ste/Cry-SMSD處方工藝。X射線粉末衍射（X-ray powder diffraction，XRPD）法分析隱丹參酮在Ste/Cry-SMSD粉末中的晶型，傅里葉變換紅外光譜（Fourier transform infrared spectroscopy，F(xiàn)T-IR）研究結(jié)合機(jī)制，透射電子顯微鏡（transmission electron microscope，TEM）觀察Ste/Cry-SMSD自組裝膠束的微觀形貌，透析袋法考察Ste/Cry-SMSD在模擬胃、腸液中釋藥情況。以隱丹參酮原料藥為參考，考察Ste/Cry-SMSD相對口服生物利用度。建立大鼠糖尿病模型，以隱丹參酮原料藥為參考，評價(jià)Ste/Cry-SMSD降血糖藥效和口服糖耐量。結(jié)果 Ste/Cry-SMSD最佳處方：甜菊素質(zhì)量濃度為2.70 mg/mL，制備溫度為52.0 ℃，攪拌時(shí)間為60.00 min。Ste/Cry-SMSD自組裝形成膠束的包封率為（94.77±0.57）%，載藥量為（8.11±0.06）%，粒徑為（8.69±0.56）nm，ζ電位為（−16.19±0.92）mV。隱丹參酮和甜菊素可能以氫鍵結(jié)合在一起，并以無定型形式存在于Ste/Cry-SMSD粉末中，Ste/Cry-SMSD在模擬胃、腸液中釋藥行為符合Weibull模型。藥動學(xué)結(jié)果顯示，Ste/Cry-SMSD達(dá)峰濃度（C_max）為（1 129.34±206.13）ng/mL，半衰期（t_1/2）延長至（4.15±0.82）h，與隱丹參酮原料藥相比相對口服吸收生物利用度提高至6.11倍。Ste/Cry-SMSD顯著增強(qiáng)了隱丹參酮降血糖藥效、血糖調(diào)節(jié)能力及口服糖耐量。結(jié)論 Ste/Cry-SMSD處方簡單，顯著增加了隱丹參酮生物利用度，并增強(qiáng)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

河南省高等學(xué)校重點(diǎn)科研項(xiàng)目（24B310010）；河南省醫(yī)學(xué)教育研究項(xiàng)目（WJLX2024191）；教育部產(chǎn)學(xué)研合作協(xié)同育人項(xiàng)目（230802175007047）