目的 使用馬來酰亞胺-聚乙二醇-聚（乳酸羥基乙酸）共聚物（Mal-PEG-PLGA）為載體制備延胡索乙素納米粒（MPPTHP-NPs），考察其口服吸收生物利用度及其對(duì)急性肝損傷模型大鼠的保護(hù)作用。方法 溶劑揮發(fā)法制備MPP-THP-NPs，根據(jù)單因素實(shí)驗(yàn)結(jié)果，選擇載藥比、水化時(shí)間、水相與有機(jī)相體積比為主要影響因素，采用包封率、載藥量和粒徑的總評(píng)歸一值（OD）為評(píng)價(jià)指標(biāo)，應(yīng)用Box-Behnken設(shè)計(jì)-效應(yīng)面法優(yōu)化MPP-THP-NPs處方工藝。測(cè)定包封率、載藥量、粒徑、多分散指數(shù)（PDI）值及ζ電位。透射電鏡（SEM）觀察微觀形貌，X射線粉末衍射法分析晶型，透析法考察MPP-THP-NPs凍干粉模擬胃腸液中體外釋藥行為。參照最優(yōu)工藝，應(yīng)用單甲氧基聚乙二醇-聚（乳酸羥基乙酸）（PEG-PLGA）制備延胡索乙素納米粒（PP-THP-NPs）。ig給予大鼠延胡索乙素、PP-THP-NPs、MPP-THP-NPs（30 mg·kg^-1，以延胡索乙素計(jì)），測(cè)定血藥濃度，考察口服相對(duì)吸收生物利用度。建立急性肝損傷模型，考察MPP-THP-NPs對(duì)急性肝損傷模型大鼠肝指數(shù)、脾指數(shù)以及血清丙氨酸氨基轉(zhuǎn)移酶（ALT）、天冬氨酸氨基轉(zhuǎn)移酶（AST）、丙二醛（MDA）和超氧化物歧化酶（SOD）水平的影響。蘇木素-伊紅（HE）染色評(píng)估大鼠肝臟組織病理變化。結(jié)果 MPP-THP-NPs最佳處方：載藥比為12.8∶ 1.0，水化時(shí)間為45 min，水相與有機(jī)相體積比為10.6∶ 1.0。MPP-THP-NPs平均包封率為（91.80±1.37）%，載藥量為（6.66±0.19）%，粒徑為（58.51±4.19） nm，ζ電位為（-18.83± 2.21） mV。MPP-THP-NPs呈球形或橢圓形，16 h累積釋放率提高至86.79%，緩釋特征明顯。藥動(dòng)學(xué)結(jié)果顯示，與延胡索乙素相比，MPP-THP-NPs相對(duì)口服生物利用度提高4.08倍，提高幅度大于PP-THP-NPs。與模型組相比，MPP-THP-NPs高劑量（30 mg·kg^-1）組肝臟指數(shù)、脾臟指數(shù)、ALT、AST、MDA水平均極顯著性下降（P＜0.01），SOD極顯著性增加（P＜0.01），且優(yōu)于延胡索乙素、PP-THP-NPs組（P＜0.05、0.01）。病理組織切片分析發(fā)現(xiàn)，MPPTHP-NPs高劑量組大鼠肝臟病理損傷顯著減輕。結(jié)論 MPP-THP-NPs極大提高了THP口服吸收生物利用度，并增強(qiáng)了THP改善急性肝損傷作用。

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

山西省中醫(yī)藥科技創(chuàng)新工程項(xiàng)目（2023kjzy009）；山西省中央引導(dǎo)地方科技發(fā)展資金項(xiàng)目（YDZJSX2024B014）