目的 制备马来酰亚胺修饰的柠檬苦素纳米粒（maleimide-modified limonin nanoparticles，Mal-Lim-NPs），对其理化性质进行表征，并研究其口服药动学行为。方法 单因素结合Box-Behnken设计-效应面法（Box-Behnken design-response surface method，BBD-RSM）优化Mal-Lim-NPs处方工艺，并制成冻干粉。X射线粉末衍射法（X-ray powder diffraction，XRPD）分析柠檬苦素在Mal-Lim-NPs冻干粉中的晶型，透射电子显微镜（transmission electron microscope，TEM）观察Mal-Lim-NPs微观外貌，测定Mal-Lim-NPs冻干粉在pH 2.0、5.0、6.8磷酸盐缓冲液（PBS）中的溶解度和释放度。SD大鼠分别ig给予柠檬苦素和Mal-Lim-NPs冻干粉，绘制血药浓度-时间曲线，计算主要药动学参数。结果 Mal-Lim-NPs最佳处方：马来酰亚胺-聚乙二醇-聚乳酸［maleimide-methoxy poly (ethylene glycol)-poly (lactic acid)，Mal-PEG-PLA］与柠檬苦素用量比为7.5∶1，水相体积为35 mL，超声时间为13 min。Mal-Lim-NPs的平均包封率、载药量、粒径和ζ电位分别为（81.63±1.30）%、（9.32±0.24）%、（171.56±6.63）nm和（−16.60±0.92）mV。柠檬苦素在Mal-Lim-NPs冻干粉中晶型状态可能发生了改变，冻干粉复溶后Mal-Lim-NPs微观外貌仍近似球形。Mal-Lim-NPs冻干粉在pH 2.0、5.0、6.8 PBS中的释药行为均符合Weibull模型。Mal-Lim-NPs达峰时间（t_max）延后至（2.61±0.40）h，末端消除半衰期（t_1/2）延长至（6.73±1.54）h，药峰浓度（C_max）和时间曲线下面积（AUC_0～t、AUC_0～¥）分别提高至柠檬苦素的4.01倍和5.65、5.89倍。结论 Mal-Lim-NPs改变了柠檬苦素体内药动学行为，显著增加了口服药物吸收，为后续研究奠定基础。

Objective To prepare maleimide-modified limonin nanoparticles (Mal-Lim-NPs), characterize its physicochemical properties, and study its oral pharmacokinetic behavior. Methods Single factor experiments combined with Box-Behnken response surface design method (BBD-RSM) was used to gain optimal prescriptions of Mal-Lim-NPs, and its lyophilized powder was prepared. Crystal form of limonin in lyophilized powder of Mal-Lim-NPs was analyzed by X-ray powder diffraction (XRPD), and microscopic appearance was observed by transmission electron microscope (TEM). Solubility and drug release rate of Mal-Lim-NPs in pH 2.0, 5.0, 6.8 phosphate buffers (PBS) were determined. SD rats in each group were administered intragastrically with limonin and Mal-Lim-NPs, respectively, blood drug concentration-time curve was plotted, and main pharmacokinetic parameters was also calculated. Results Optimal prescriptions of Lin-Mal-NP: Mal-PEG-PLA to limonin dosage ratio was 7.5:1, water phase volume was 35 mL and ultrasonic time was 13 min. Average envelopment efficiency, drug loading, particle size and ζ potential were (81.63 ±1.30)%, (9.32 ±0.24)%, (171.56 ±6.63) nm and (−16.60 ±0.92) mV, respectively. The crystalline state of limonin maybe changed in Mal-Lim-NPs lyophilized powder. Microcosmic appearance of Mal-Lim-NPs was still nearly spherical after dissolved by water. The release behavior of Mal-Lim-NPs in pH 2.0, 5.0, 6.8 PBS were in accordance with Weibull model. The t_max of Mal-Lim-NPs delayed to (2.61 ±0.40) h, t_1/2 was increased to (6.73 ±1.54) h, C_max and AUC_0—t, AUC_0—¥ were increased to 4.01-fold and 5.65, 5.89-fold, respectively. Conclusion Mal-Lim-NPs changed the pharmacokinetic behavior of limonin in vivo and significantly increased the oral absorption, which laid foundation for the following research.

R283.6

河南省高等学校重点科研项目（23B310015）