目的 使用茶皂素作为稳定剂制备金合欢素纳米混悬剂（Ts-Aca-NPs），考察口服相对吸收生物利用度和对高脂血症模型大鼠的治疗作用。方法 高压均质法制备Ts-Aca-NPs。选择茶皂素质量浓度、均质压力和均质次数为主要影响因素，单因素结合Box-Behnken设计-效应面法（BBD-RSM）优化Ts-Aca-NPs处方工艺。测定Ts-Aca-NPs粒径，多分散指数（PDI）值及ζ电位，扫描电镜（SEM）观察Ts-Aca-NPs微观形貌，X射线粉末衍射法（XRPD）分析晶型，透析法考察Ts-Aca-NPs冻干粉在pH 2.0、pH 6.8磷酸盐缓冲液及水中的释药行为。ig给予大鼠金合欢素和Ts-Aca-NPs（50 mg·kg^-1，以金合欢素计），测定血药浓度，考察口服相对吸收生物利用度。建立大鼠高脂血症模型，考察Ts-Aca-NPs对高脂血症大鼠体质量、肝系数以及血清总胆固醇（TC）、三酰甘油（TG）、低密度胆固醇（LDL-C）、高密度胆固醇（HDL-C）、天冬氨酸氨基转移酶（AST）及丙氨酸氨基转移酶（ALT）的影响。结果 Ts-Aca-NPs最佳处方工艺：茶皂素质量分数为0.13%，均质压力为95 MPa，均质次数为10次。Ts-Aca-NPs平均粒径为（301.81±4.74） nm，PDI值为0.103± 0.003，ζ电位为（-23.17±1.19） mV。Ts-Aca-NPs形貌为不规则的纳米颗粒，金合欢素在Ts-Aca-NPs冻干粉以晶态存在，结晶度有所下降。Ts-Aca-NPs极大提高了金合欢素在不同pH磷酸盐缓冲液中的溶解度，Ts-Aca-NPs在pH 2.0、pH 6.8磷酸盐缓冲液及水中12 h累积溶出度均大于90%。与金合欢素比较，Ts-Aca-NPs半衰期（t_1/2）延长至（3.09± 0.42） h，AUC_0~t增加至（1 294.81± 243.06） ng·h·mL^-1，相对口服吸收生物利用度提高至6.03倍。与模型组比较，Ts-Aca-NPs高剂量组（50 mg·kg^-1）体质量、肝系数、TC、TG、LDL-C、ALT和AST均显著性下降（P＜0.05、0.01），HDL-C显著性升高（P＜0.05），且治疗作用明显优于金合欢素原料药组（50 mg·kg^-1）。结论 Ts-Aca-NPs极大提高了金合欢素的溶解度及溶出度，有效提高了金合欢素生物利用度及调血脂作用。

Objective To prepare tea saponin-acacetin nanosuspensions (Ts-Aca-NPs) using tea saponin as stabilizer, and investigate its relative oral bioavailability and therapeutic effects on hyperlipidemia model rats. Methods High pressure homogenization method was used to prepare Ts-Aca-NPs. The concentration of tea saponin, homogenization pressure, and homogenization times were selected as the main influencing factors, single factor experiments combined with Box-Behnken response surface design method (BBD-RSM) were used to optimize the optimal prescription process of Ts-Aca-NPs. Particle size, PDI value and ζ potential of Ts-Aca-NPs were determined. Microscopic morphology was observed by scanning electron microscope (SEM). Crystal form was analyzed by X-ray powder diffraction (XRPD). Dialysis method was used to investigate the drug release behavior of Ts-Aca-NPs in pH 2.0, pH 6.8 phosphate buffer and water. Acacetin and Ts-Aca-NPs were administered orally (50 mg·kg^-1, calculated by acacetin), blood drug concentration was determined, and the relative oral bioavailability was investigated. hyperlipidemia rats model was established, and studied the effects of Ts-Aca-NPs on the body weight, liver coefficient, total cholesterol (TC), triglyides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Results Optimal prescription process of Ts-Aca-NPs: the concentration of tea saponin was 0.13%, homogenization pressure was 95 Mpa, and homogenization times was ten. Particle size, PDI and ζ potential of Ts-Aca-NPs were (301.81 ± 4.74) nm, 0.103 ± 0.003 and (-23.17 ± 1.19) mV, respectively. The morphology of Ts-Aca-NPs was irregular nanoparticles. Acacetin existed as crystalline form in the lyophilized powder of Ts-Aca-NPs, and the crystallinity of acacetin decreased slightly. Ts-Aca-NPs significantly increased the solubility of acacetin in different pH phosphate buffer, and the cumulative dissolution of Ts-Aca-NPs in pH 2.0, pH 6.8 phosphate buffer and water were more than 90% in 12 h. Compared with acacetin, The t_1/2 of Ts-Aca-NPs was enhanced to (3.09 ± 0.42) h, AUC_0~t was increased to (1 294.81 ± 243.06) ng·mL^-1·h, and relative oral bioavailability was enhanced to 6.03 times. Compared with model group, high-dose of Ts-Aca-NPs (50 mg·kg^-1) could effectively decreased body weight, liver coefficient, TC, TG, LDL-C, ALT and AST (P < 0.05, 0.01), and significantly increased HDL-C (P < 0.05), and its therapeutic effects was better than that of acacetin (50 mg·kg^-1). Conclusion Ts-Aca-NPs significantly improved the solubility and dissolution of acacetin, and effectively promoted bioavailability and hypolipidemic effects of acacetin in vivo.

R943

河南省高等学校重点科研项目计划（23B310010）；新疆科技学院科研基金创新团队专项（2024-KYTD02）；郑州市澍青医学高等专科学校青年骨干教师（2022qngg04）