目的 制備高良姜素自膠束化固體分散體（Gal-SMSD），考察其相對生物利用度和降血糖作用。方法 以Gal-SMSD自組裝膠束的包封率、載藥量和沉降率為指標(biāo)，單因素試驗結(jié)合Box-Behnken設(shè)計-效應(yīng)面法優(yōu)化Gal-SMSD處方工藝。透射電鏡（TEM）觀察自組裝膠束形貌，X射線粉末衍射法（XRPD）分析晶型，傅里葉紅外光譜法（FTIR）研究結(jié)合機制。透析袋法考察Gal-SMSD在模擬胃腸液中釋藥行為。以高良姜素為對比，比較Gal-SMSD口服藥動學(xué)行為。構(gòu)建大鼠2型糖尿?。═2DM）模型，考察高良姜素（50 mg·kg^-1）和Gal-SMSD低、中、高劑量（10、30、50 mg·kg^-1）對T2DM小鼠血糖、血清天冬氨酸氨基轉(zhuǎn)移酶（AST）、丙氨酸氨基轉(zhuǎn)移酶（ALT）、尿素氮（BUN）和肌酸酐（Crea）水平、口服糖耐量的影響。結(jié)果 Gal-SMSD最佳處方：載藥比7.05∶1，制備溫度為51.00 ℃，制備時間為2.00 h。Gal-SMSD自組裝形成膠束包封率為（93.47±1.19）%，載藥量為（11.62±0.20）%，沉降率為（1.36±0.13）%，粒徑為（66.19±4.33）nm，Zeta電位為（-11.74±0.95）mV。Gal-SMSD自組裝膠束呈類球形，高良姜素以無定型形式存在于Gal-SMSD粉末中，高良姜素和mPEG-PLA之間可能發(fā)生了氫鍵結(jié)合力。Gal-SMSD體外行為符合Weibull模型，12 h累積釋放率提高至84.16%。藥動學(xué)結(jié)果顯示Gal-SMSD達峰濃度（C_max）為（1 669.78±306.13）ng·mL^-1，半衰期（t_1/2）延長至（4.77±0.91）h，相對口服吸收生物利用度提高至高良姜素的5.16倍。與模型組比較，Gal-SMSD高劑量（50 mg·kg^-1）可使T2DM小鼠血糖顯著下降，血清AST、ALT、BUN、Crea水平均顯著降低（P＜0.05、0.01），并顯著改善耐糖量，效果明顯好于高良姜素（50 mg·kg^-1）。結(jié)論 Gal-SMSD可促進高良姜素體內(nèi)口服吸收，增強對T2DM小鼠的降血糖作用。

Objective To prepare galangin-loaded self-micelle solid dispersion (Gal-SMSD), relative bioavailability and glucose-decreasing effects in vivo were investigated. Methods Encapsulation efficiency, drug loading and sedimentation rate of self-assembled micelles of Gal-SMSD were acted as evaluation indexes, formulation of Gal-SMSD was optimized though single factor experiment and Box-Behnken design-response surface method. Morphology of self-assembled micelles was observed by transmission electron microscopy (TEM), galangin crystal form in Gal-SMSD powder was analyzed by X-ray powder diffraction (XRPD), fourier infrared spectroscopy (FTIR) was used to study the binding mechanism. Drug release behavior of Gal-SMSD in simulated gastrointestinal fluid were also investigated. Oral pharmacokinetic behavior of Gal-SMSD was compared in contrast to galangin. The model of type 2 diabetes mellitus (T2DM) in rats was established to investigate the effects of galangin (50 mg·kg^-1) and Gal-SMSD at low, medium and high doses (10, 30, 50 mg·kg^-1) on blood glucose, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea nitrogen (BUN), creatinine (Crea) levels, and oral glucose tolerance in T2DM mice. Results Optimal preparation of Gal-SMSD: carrier to drug ratio was 7.05∶1, preparation temperature was 51.00 ℃ and preparation time was 2.00 h. Encapsulation efficiency, drug loading, sedimentation rate, particle size and Zeta potential of the self-assembled micelles were (93.47 ±1.19)%, (11.62 ±0.20)%, (1.36 ±0.13)%, (66.19 ±4.33) nm and (–11.74 ±0.95) mV, respectively. The shape of self-assembled micelles was spherical, and galangin existed as an amorphous form in Gal-SMSD powder. There might be a hydrogen bonding between galangin and mPEG-PLA. The release behavior of Gal-SMSD was in accordance with Weibull model, and the cumulative release rate increased to 84.16% in 12 h. Pharmacokinetic results showed that C_max of Gal-SMSD was increased to (1 669.78 ±306.13) ng·mL^-1, t_1/2 was prolonged to (4.77 ±0.91) h, and its relative bioavailability was increased to 5.16 times that of galangin. Compared with the model group, high doses of GAL-SMSD (50 mg·kg^-1) significantly reduced blood glucose levels, serum AST, SLT, BUN, and Crea levels in T2DM mice (P < 0.05, 0.01), and significantly improved glucose tolerance, with a significantly better effect than the galangin (50 mg·kg^-1) group. Conclusion Gal-SMSD could promote oral absorption of galangin in vivo, and significantly decrease blood glucose in T2DM mice.

R943

上海市科委項目（21S21903400）