目的 制备高良姜素自胶束化固体分散体（Gal-SMSD），考察其相对生物利用度和降血糖作用。方法 以Gal-SMSD自组装胶束的包封率、载药量和沉降率为指标，单因素试验结合Box-Behnken设计-效应面法优化Gal-SMSD处方工艺。透射电镜（TEM）观察自组装胶束形貌，X射线粉末衍射法（XRPD）分析晶型，傅里叶红外光谱法（FTIR）研究结合机制。透析袋法考察Gal-SMSD在模拟胃肠液中释药行为。以高良姜素为对比，比较Gal-SMSD口服药动学行为。构建大鼠2型糖尿病（T2DM）模型，考察高良姜素（50 mg·kg^-1）和Gal-SMSD低、中、高剂量（10、30、50 mg·kg^-1）对T2DM小鼠血糖、血清天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、尿素氮（BUN）和肌酸酐（Crea）水平、口服糖耐量的影响。结果 Gal-SMSD最佳处方：载药比7.05∶1，制备温度为51.00 ℃，制备时间为2.00 h。Gal-SMSD自组装形成胶束包封率为（93.47±1.19）%，载药量为（11.62±0.20）%，沉降率为（1.36±0.13）%，粒径为（66.19±4.33）nm，Zeta电位为（-11.74±0.95）mV。Gal-SMSD自组装胶束呈类球形，高良姜素以无定型形式存在于Gal-SMSD粉末中，高良姜素和mPEG-PLA之间可能发生了氢键结合力。Gal-SMSD体外行为符合Weibull模型，12 h累积释放率提高至84.16%。药动学结果显示Gal-SMSD达峰浓度（C_max）为（1 669.78±306.13）ng·mL^-1，半衰期（t_1/2）延长至（4.77±0.91）h，相对口服吸收生物利用度提高至高良姜素的5.16倍。与模型组比较，Gal-SMSD高剂量（50 mg·kg^-1）可使T2DM小鼠血糖显著下降，血清AST、ALT、BUN、Crea水平均显著降低（P＜0.05、0.01），并显著改善耐糖量，效果明显好于高良姜素（50 mg·kg^-1）。结论 Gal-SMSD可促进高良姜素体内口服吸收，增强对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

上海市科委项目（21S21903400）