目的 制備馬來酰亞胺修飾的檸檬苦素納米粒（maleimide-modified limonin nanoparticles，Mal-Lim-NPs），對其理化性質(zhì)進行表征，并研究其口服藥動學行為。方法 單因素結合Box-Behnken設計-效應面法（Box-Behnken design-response surface method，BBD-RSM）優(yōu)化Mal-Lim-NPs處方工藝，并制成凍干粉。X射線粉末衍射法（X-ray powder diffraction，XRPD）分析檸檬苦素在Mal-Lim-NPs凍干粉中的晶型，透射電子顯微鏡（transmission electron microscope，TEM）觀察Mal-Lim-NPs微觀外貌，測定Mal-Lim-NPs凍干粉在pH 2.0、5.0、6.8磷酸鹽緩沖液（PBS）中的溶解度和釋放度。SD大鼠分別ig給予檸檬苦素和Mal-Lim-NPs凍干粉，繪制血藥濃度-時間曲線，計算主要藥動學參數(shù)。結果 Mal-Lim-NPs最佳處方：馬來酰亞胺-聚乙二醇-聚乳酸［maleimide-methoxy poly (ethylene glycol)-poly (lactic acid)，Mal-PEG-PLA］與檸檬苦素用量比為7.5∶1，水相體積為35 mL，超聲時間為13 min。Mal-Lim-NPs的平均包封率、載藥量、粒徑和ζ電位分別為（81.63±1.30）%、（9.32±0.24）%、（171.56±6.63）nm和（−16.60±0.92）mV。檸檬苦素在Mal-Lim-NPs凍干粉中晶型狀態(tài)可能發(fā)生了改變，凍干粉復溶后Mal-Lim-NPs微觀外貌仍近似球形。Mal-Lim-NPs凍干粉在pH 2.0、5.0、6.8 PBS中的釋藥行為均符合Weibull模型。Mal-Lim-NPs達峰時間（t_max）延后至（2.61±0.40）h，末端消除半衰期（t_1/2）延長至（6.73±1.54）h，藥峰濃度（C_max）和時間曲線下面積（AUC_0～t、AUC_0～¥）分別提高至檸檬苦素的4.01倍和5.65、5.89倍。結論 Mal-Lim-NPs改變了檸檬苦素體內(nèi)藥動學行為，顯著增加了口服藥物吸收，為后續(xù)研究奠定基礎。

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

河南省高等學校重點科研項目（23B310015）