目的 优化聚乙二醇修饰高良姜素纳米结构脂质载体（pegylated gallerythrine nanostructured lipid carriers，PEG-Gal-NLCs）处方，并进行体外释药行为和体内药动学评价。方法 采用乳化法制备PEG-Gal-NLCs。Box-Behnken设计-效应面法（Box Behnken design-response surface methodology，BBD-RSM）筛选PEG-Gal-NLCs最优处方，测定包封率、载药量、粒径及ζ电位。将PEG-Gal-NLCs混悬液制备成冻干粉，X射线粉末衍射（X-ray powder diffraction，XRPD）法分析高良姜素在PEG-Gal-NLCs冻干粉中的存在形式。考察PEG-Gal-NLCs冻干粉在模拟胃肠液中的释药行为，并对释药模型进行拟合。SD大鼠按50 mg/kg剂量ig后采血，HPLC法测定血药浓度，计算主要药动学参数及相对生物利用度。结果 PEG-Gal-NLCs最佳处方为聚乙二醇-单硬脂酸酯（PEG₂₀₀₀-SA）占载体的质量分数为16%、载体与药物比例为13.5∶1、固-液脂质比例为3.6∶1。PEG-Gal-NLCs的包封率为（92.75±1.38）%，载药量为（6.44±0.23）%，平均粒径为（181.05±8.62）nm，ζ电位为（−30.71±1.56）mV。XRPD分析结果表明，高良姜素在PEG-Gal-NLCs冻干粉中以无定形状态存在。PEG-Gal-NLCs冻干粉在模拟胃肠液中体外释药具有缓释特征，释药过程均符合Weibull模型。PEG-Gal-NLCs的半衰期（t_1/2）增加至（4.82±0.93）h，血药浓度（C_max）增加至（1.43±0.42）μg/mL，口服相对生物利用度提高至4.28倍。结论 PEG-Gal-NLCs显著增加了高良姜素口服吸收。

Objective To optimize prescriptions of pegylated gallerythrine nanostructured lipid carriers (PEG-Gal-NLCs), and carry out drug release behavior in vitro and oral pharmacokinetics in vivo evaluation. Methods Emulsification method was employed to prepare PEG-Gal-NLCs. Box-Behnken design-response surface methodology (BBD-RSM) was used to investigate the optimal prescriptions of PEG-Gal-NLCs. Entrapment efficiency, drug loading, particle size and ζ potential of PEG-Gal-NLCs were determined. Lyophilized powder of PEG-Gal-NLCs was prepared. The existence of Gal in PEG-Gal-NLCs lyophilized powder was analyzed by X-ray powder diffraction (XRPD). In vitro release behavior of PEG-Gal-NLCs lyophilized powder in simulate gastrointestinal fluid was investigated, and the release model was fitted. SD rats were administered intragastrically at a dose of 50 mg/kg and blood samples were collected. Plasma concentrations were determined by HPLC, and main pharmacokinetic parameters and relative bioavailability were calculated. Results Optimal formulation of PEG-Gal-NLCs:content of PEG₂₀₀₀-SA in carriers was 16%, ratio of carriers to drug was 13.5:1, and solid to liquid lipid ratio was 3.6:1. Envelopment efficiency, drug loading, particle size and ζ potential were (92.75 ±1.38)%, (6.44 ±0.23)%, (181.05 ±8.62) nm and (−30.71 ±1.56) mV, respectively. Gal existed as an amorphous state in PEG-Gal-NLCs lyophilized powder. The drug release in vitro has obvious sustained-release characteristics in simulate gastrointestinal fluid, and the release process conformed to the Weibull model. The t_1/2 of PEG-Gal-NLCs was increased to (4.82 ±0.93) h, C_max was enhanced to (1.43 ±0.42) μg/mL and oral relative bioavailability was increased to 4.28-fold. Conclusion PEG-Gal-NLCs can promote oral absorption of Gal effectively.

R283.6

国家“重大新药创制”（2018ZX09201009-002-09）；教育部产学合作协同育人项目（202102028026）；教育部产学合作协同育人项目（202101021046）