目的 Box-Behnken设计-效应面法优化白屈菜红碱单甲氧基聚乙二醇-聚乳酸羟基乙酸共聚物（methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid，mPEG-PLGA）纳米粒［chelerythrine mPEG-PLGA nanoparticles，Che@mPEG-PLGA/NPs］处方，并对最佳处方进行体外评价及体内药动学研究。方法 纳米沉淀法制备Che@mPEG-PLGA/NPs，以包封率、载药量和粒径为指标，采用单因素试验结合Box-Behnken设计-效应面法筛选Che@mPEG-PLGA/NPs的最佳处方。将Che@mPEGPLGA/NPs混悬液进一步制备成冻干粉，并考察冻干粉的稳定性和体外释药行为。SD大鼠分为Che原料药组、物理混合物组和Che@mPEG-PLGA/NPs组，分别按20mg/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 Che@mPEG-PLGA/NPs最佳处方为mPEG-PLGA用量572mg、水相与有机相的体积比为2.3∶1、泊洛沙姆188用量为1.2%。Che@mPEG-PLGA/NPs的包封率为（83.49±1.59）%，载药量为（4.61±0.14）%，粒径为（163.93±8.02）nm。Che@mPEG-PLGA/NPs在不同pH值释药介质中的体外释药具有明显的缓释特征。药动学结果显示，Che@mPEGPLGA/NPs的达峰时间（t_max）延后至（2.12±0.46）h，半衰期（t_1/2）延长至（5.66±0.93）h，达峰浓度（C_max）增加至4.49倍，相对口服吸收生物利用度提高至4.66倍。结论 Che@mPEG-PLGA/NPs可显著提高Che的口服吸收生物利用度，值得进一步研究。

Objective Box-Behnken design-response surface method was employed to optimize the formulation of chelerythrine methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid (mPEG-PLGA) nanoparticles (Che@mPEG-PLGA/NPs), and carry out in vitro evaluation and oral pharmacokinetics study of optimal prescriptions.Methods Nano-precipitation method was employed to prepare Che@mPEG-PLGA/NPs. Encapsulation rate, drug loading and particle size were used as evaluation indexes, single factor investigation method combined with Box-Behnken response surface design method was combined to investigate the optimal prescriptions of Che@mPEG-PLGA/NPs, and then its lyophilized powder was prepared. Stability and release behavior in vitro of lyophilized powder was investigated. SD rats were divided into Che suspension, physical mixture and Che@mPEG-PLGA/NPs groups, blood samples were collected after gastric administration at a dose of 20 mg/kg. The plasma concentrations were determined by HPLC, main pharmacokinetic parameters and relative bioavailability were calculated.Results The optimal formulation of Che@ mPEGPLGA/NPs: mPEG-PLGA dosage was 572 mg, water phase to organic phase volume ratio was 2.3∶1 and concentration of poloxamer 188 was 1.2%. Envelopment efficiency, drug loading and particle size of Che@mPEG-PLGA/NPs were (83.49 ±1.59)%, (4.61 ±0.14)% and (163.93 ±8.02) nm. Drug release in vitro had obvious sustained-release characteristics in different pH dissolution media. Pharmacokinetic results showed that t_max of Che@mPEG-PLGA/NPs was delayed to (2.12 ±0.46) h, t_1/2 was prolonged to (5.66 ±0.93) h, C_max was increased to 4.49 times and relative oral bioavailability was enhanced to 4.66 times.Conclusion Che@mPEG-PLGA/NPs can significantly improve the oral bioavailability of Che, which was worthy of further study.

R283.6

国家自然科学青年基金资助项目(51804021)