丹酚酸B、丹参酮ⅡA、甘草次酸口服乳剂制备及其对对乙酰氨基酚诱导急性肝损伤的保护作用研究  

Preparation of salvianolic acid B, tanshinone ⅡA, and glycyrrhetinic acid lipid emulsion and its protective effect against acute liver injury induced by acetaminophen

作　　者：张秀荣[1] 林涛 王秀丽[1] 王晓杰[2] 顾蘅[3] ZHANG Xiu-rong;LIN Tao;WANG Xiu-li;WANG Xiao-jie;GU Heng(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 102488,China;Collge of Bioengineering,Bejing Polytechnic,Beijing 100176,China;TCM Pharmacy,Kunming Municipal Hospital of Traditional Chinese Medicine,Kunming 65001l,China)

机构地区：[1]北京中医药大学中药学院,北京102488 [2]北京电子科技职业学院生物工程学院,北京100176 [3]昆明市中医医院中药房,云南昆明650011

出　　处：《中国中药杂志》2022年第17期4634-4642,共9页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81202928);促进高校内涵建设-师资队伍建设-“高创计划”教学名师项目(CJGX2017-SZJS-006)。

摘　　要：采用高速分散法结合超声乳化法制备丹酚酸B、丹参酮Ⅱ、甘草次酸口服乳剂(GTS-LE),以乳剂外观,离心稳定性及粒径为评价指标,运用单因素法及D-optimal优化乳剂制备工艺并进行验证;反向透析法进行GTS-LE中丹酚酸B(Sal B)、丹参酮Ⅱ(TSNⅡ)及甘草次酸(GA)的体外释放过程;进行小鼠体内药代动力学评价;建立对乙酰氨基酚诱导急性肝损伤模型,通过小鼠血清肝功能指标,肝组织病理变化,考察口服乳剂对药物急性肝损伤的影响。结果以最佳工艺制备的GTS-LE平均粒径为(145.4±9.25)nm, Zeta电位为(-33.6±1.45)mV。GTS-LE中Sal B、TSNⅡ、GA的3种药物载药效率均高达95%以上,体外释药均符合Higuchi方程。药代动力学结果显示,GTS-LE中Sal B的C及AUC分别是原药混悬液组的3.128、3.09倍,TSNⅡ的C及AUC分别为其的2.7、2.23倍,GA的C及AUC分别为其的2.85、1.9倍。小鼠灌胃GTS-LE后,可明显抑制丙氨酸转氨酶、天门冬氨基转氨酶活性,降低丙二醛含量,且肝细胞结构趋于正常。综上所述,GTS-LE可延缓Sal B释放,促进TSNⅡ,GA释放;3种药物成分经过乳剂的包载可不同程度地提高其口服生物利用度,且能够有效预防对乙酰氨基酚导致的药物急性肝损伤。Salvianolic acid B(Sal B), tanshinone Ⅱ(TSN Ⅱ), and glycyrrhetinic acid(GA) lipid emulsion(GTS-LE) was prepared by the high-speed dispersion method combined with ultrasonic emulsification.The preparation process of the emulsion was optimized by single-factor method and D-optimal method with appearance, centrifugal stability, and particle size of the emulsion as evalua-tion indexes, followed by verification.In vitro release of Sal B, TSN Ⅱ, and GA in GTS-LE was performed by reverse dialysis.In vivo pharmacokinetic evaluation was carried out in mice.The acute liver injury model was induced by acetaminophen.The effect of oral GTS-LE on the acute liver injury was investigated by serum liver function indexes and pathological changes in liver tissues of mice.The results showed that under the optimal preparation process, the average particle size of GTS-LE was(145.4±9.25) nm and the Zeta potential was(-33.6±1.45) mV.The drug-loading efficiencies of Sal B, TSN Ⅱ, and GA in GTS-LE were above 95%, and the drug release in vitro conformed to the Higuchi equation.The pharmacokinetic results showed that the Cof Sal B, TSN Ⅱ, and GA in GTS-LE was 3.128, 2.7, and 2.85 times that of the GTS-S group, and AUCof Sal B, TSN Ⅱ, and GA in GTS-LE was 3.09, 2.23, and 1.9 times that of the GTS-S group.After intragastric administration of GTS-LE, the activities of alanine aminotransferase and aspartate aminotransferase were significantly inhibited, the content of malondialdehyde was reduced, and the structure of hepatocytes recovered to normal.In conclusion, GTS-LE can delay the release of Sal B and promote the release of TSN Ⅱand GA.The encapsulation of three drug components in the emulsion can improve the oral bioavailability to varying degrees and can effectively prevent the acute liver injury caused by acetaminophen.

关 键 词：急性肝损伤 对乙酰氨基酚 丹酚酸B 丹参酮ⅡA 甘草次酸 乳剂 

分 类 号：R285.5[医药卫生—中药学] R283.6[医药卫生—中医学]