目的 使用茶皂素作為穩(wěn)定劑制備金合歡素納米混懸劑（Ts-Aca-NPs），考察口服相對(duì)吸收生物利用度和對(duì)高脂血癥模型大鼠的治療作用。方法 高壓均質(zhì)法制備Ts-Aca-NPs。選擇茶皂素質(zhì)量濃度、均質(zhì)壓力和均質(zhì)次數(shù)為主要影響因素，單因素結(jié)合Box-Behnken設(shè)計(jì)-效應(yīng)面法（BBD-RSM）優(yōu)化Ts-Aca-NPs處方工藝。測(cè)定Ts-Aca-NPs粒徑，多分散指數(shù)（PDI）值及ζ電位，掃描電鏡（SEM）觀察Ts-Aca-NPs微觀形貌，X射線粉末衍射法（XRPD）分析晶型，透析法考察Ts-Aca-NPs凍干粉在pH 2.0、pH 6.8磷酸鹽緩沖液及水中的釋藥行為。ig給予大鼠金合歡素和Ts-Aca-NPs（50 mg·kg^-1，以金合歡素計(jì)），測(cè)定血藥濃度，考察口服相對(duì)吸收生物利用度。建立大鼠高脂血癥模型，考察Ts-Aca-NPs對(duì)高脂血癥大鼠體質(zhì)量、肝系數(shù)以及血清總膽固醇（TC）、三酰甘油（TG）、低密度膽固醇（LDL-C）、高密度膽固醇（HDL-C）、天冬氨酸氨基轉(zhuǎn)移酶（AST）及丙氨酸氨基轉(zhuǎn)移酶（ALT）的影響。結(jié)果 Ts-Aca-NPs最佳處方工藝：茶皂素質(zhì)量分?jǐn)?shù)為0.13%，均質(zhì)壓力為95 MPa，均質(zhì)次數(shù)為10次。Ts-Aca-NPs平均粒徑為（301.81±4.74） nm，PDI值為0.103± 0.003，ζ電位為（-23.17±1.19） mV。Ts-Aca-NPs形貌為不規(guī)則的納米顆粒，金合歡素在Ts-Aca-NPs凍干粉以晶態(tài)存在，結(jié)晶度有所下降。Ts-Aca-NPs極大提高了金合歡素在不同pH磷酸鹽緩沖液中的溶解度，Ts-Aca-NPs在pH 2.0、pH 6.8磷酸鹽緩沖液及水中12 h累積溶出度均大于90%。與金合歡素比較，Ts-Aca-NPs半衰期（t_1/2）延長(zhǎng)至（3.09± 0.42） h，AUC_0~t增加至（1 294.81± 243.06） ng·h·mL^-1，相對(duì)口服吸收生物利用度提高至6.03倍。與模型組比較，Ts-Aca-NPs高劑量組（50 mg·kg^-1）體質(zhì)量、肝系數(shù)、TC、TG、LDL-C、ALT和AST均顯著性下降（P＜0.05、0.01），HDL-C顯著性升高（P＜0.05），且治療作用明顯優(yōu)于金合歡素原料藥組（50 mg·kg^-1）。結(jié)論 Ts-Aca-NPs極大提高了金合歡素的溶解度及溶出度，有效提高了金合歡素生物利用度及調(diào)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

河南省高等學(xué)校重點(diǎn)科研項(xiàng)目計(jì)劃（23B310010）；新疆科技學(xué)院科研基金創(chuàng)新團(tuán)隊(duì)專項(xiàng)（2024-KYTD02）；鄭州市澍青醫(yī)學(xué)高等?？茖W(xué)校青年骨干教師（2022qngg04）