目的 使用马来酰亚胺-聚乙二醇-聚（乳酸羟基乙酸）共聚物（Mal-PEG-PLGA）为载体制备延胡索乙素纳米粒（MPPTHP-NPs），考察其口服吸收生物利用度及其对急性肝损伤模型大鼠的保护作用。方法 溶剂挥发法制备MPP-THP-NPs，根据单因素实验结果，选择载药比、水化时间、水相与有机相体积比为主要影响因素，采用包封率、载药量和粒径的总评归一值（OD）为评价指标，应用Box-Behnken设计-效应面法优化MPP-THP-NPs处方工艺。测定包封率、载药量、粒径、多分散指数（PDI）值及ζ电位。透射电镜（SEM）观察微观形貌，X射线粉末衍射法分析晶型，透析法考察MPP-THP-NPs冻干粉模拟胃肠液中体外释药行为。参照最优工艺，应用单甲氧基聚乙二醇-聚（乳酸羟基乙酸）（PEG-PLGA）制备延胡索乙素纳米粒（PP-THP-NPs）。ig给予大鼠延胡索乙素、PP-THP-NPs、MPP-THP-NPs（30 mg·kg^-1，以延胡索乙素计），测定血药浓度，考察口服相对吸收生物利用度。建立急性肝损伤模型，考察MPP-THP-NPs对急性肝损伤模型大鼠肝指数、脾指数以及血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、丙二醛（MDA）和超氧化物歧化酶（SOD）水平的影响。苏木素-伊红（HE）染色评估大鼠肝脏组织病理变化。结果 MPP-THP-NPs最佳处方：载药比为12.8∶ 1.0，水化时间为45 min，水相与有机相体积比为10.6∶ 1.0。MPP-THP-NPs平均包封率为（91.80±1.37）%，载药量为（6.66±0.19）%，粒径为（58.51±4.19） nm，ζ电位为（-18.83± 2.21） mV。MPP-THP-NPs呈球形或椭圆形，16 h累积释放率提高至86.79%，缓释特征明显。药动学结果显示，与延胡索乙素相比，MPP-THP-NPs相对口服生物利用度提高4.08倍，提高幅度大于PP-THP-NPs。与模型组相比，MPP-THP-NPs高剂量（30 mg·kg^-1）组肝脏指数、脾脏指数、ALT、AST、MDA水平均极显著性下降（P＜0.01），SOD极显著性增加（P＜0.01），且优于延胡索乙素、PP-THP-NPs组（P＜0.05、0.01）。病理组织切片分析发现，MPPTHP-NPs高剂量组大鼠肝脏病理损伤显著减轻。结论 MPP-THP-NPs极大提高了THP口服吸收生物利用度，并增强了THP改善急性肝损伤作用。

Objective To prepare maleimide-modified tetrahydropalmatine nanoparticles (MPP-THP-NPs) using maleimidepoly(ethylene glycol)-poly(lactic-co-glycolic acid) copolymer (Mal-PEG-PLGA) as carrier, and investigate its oral bioavailability and protective effects on acute liver injury. Methods Solvent evaporation method was employed to prepare MPP-THP-NPs. According to results of single factor experiments, carrier to drug ratio, hydration time, and volume ratio of water phase to organic phase selected were acted as main influencing factors, the overall desirability (OD) was used as evaluation index, Box-Behnken response surface design method was used to optimize its prescription process. Encapsulation efficiency, drug loading, particle size and ζ potential were determined. Transmission electron microscopy (TEM) was used to observe the micro-appearance of MPP-THP-NPs, X-ray powder diffraction (XRPD) method was used to analyze the crystal form, and the dialysis method was used to investigate the in vitro drug release behavior of MPP-THP-NPs freeze-dried powder in simulated gastrointestinal fluids. According to the optimal process of MPPTHP-NPs, tetrahydropalmatine nanoparticles (PP-THP-NPs) were prepared by using methoxy polyethylene glycol-poly (lactic acidco-gcolic acid) (PEG-PLGA). TMP, PP-THP-NPs, and MPP-THP-NPs were given at a dose of 30 mg·kg^-1 (calculated by THP), the blood concentration of THP was determined, the relative bioavailability of MPP-THP-NPs was also calculated. The model of acute liver injury was established, the effects of MPP-THP-NPs on the spleen coefficient, liver coefficient, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), and superoxide dismutase (SOD) of serum in rats were investigated. Hematoxylin-eosin (HE) staining was used to evaluate the pathological changes in rat liver tissue. Results The optimal prescription process of MPP-THP-NPs was as follows: carrier to drug ratio was 12.8∶ 1.0, hydration time was 45 min, and volume ratio of water phase to organic phase was 10.6∶ 1.0. MPP-THP-NPs shared average encapsulation efficiency of (91.80 ± 1.37) %, drug loading of (6.66 ± 0.19) %, particle size of (58.51 ± 4.19) nm and ζ potential was (-18.83 ± 2.21) mV. MPP-THP-NPs were spherical or elliptical in shape, cumulative dissolution rate of MPP-THP-NPs was enhanced to 86.79% in 16 h, and the characteristics of sustained-release were obvious. Pharmacokinetic results showed that oral bioavailability of MPP-THP-NPs were increased to 4.08 times, and its enhancement degree was greater than that of PP-THP-NPs. Compared with THP group (30 mg·kg^-1), liver index, spleen index, ALT, AST, and MDA of MPP-THP-NPs (30 mg·kg^-1) group extremely significantly decreased (P < 0.01), and SOD was extremely significantly increased (P < 0.01), these effects were better than that of THP and PP-THP-NPs group (P < 0.05, 0.01). HE staining results of liver tissue showed that the pathological injury of rat liver in the high-dose group of MPP-THP-NPs was significantly reduced. Conclusion MPP-THP-NPs greatly enhanced the oral bioavailability of THP, and enhanced the effect of THP on improving acute liver injury.

R943

山西省中医药科技创新工程项目（2023kjzy009）；山西省中央引导地方科技发展资金项目（YDZJSX2024B014）