基于Ⅰ相代谢调控的葛根素微乳的制备及其药动学研究  

Study on Preparation and Pharmacokinetics of Puerarin Microemulsion Based on Phase Ⅰ Metabolic Regulation

作　　者：代丽萍 李维 卓虹伊 刘贵容 贺艳 胡一晨 宋雨 邹亮[2,4] DAI Liping;LI Wei;ZHUO Hongyi;LIU Guirong;HE Yan;HU Yichen;SONG Yu;ZOU Liang(Sichuan Institute of Antibiotics, Chengdu University, Chengdu 610052, China;School of Medicine, Chengdu University,Chengdu 610106,China;School of Pharmacy,Chengdu University of TCM,Chengdu 611137,China;Key Lab of Grain Processing,Ministry of Agriculture,School of Pharmacy and Bioengineering,Chengdu University,Chengdu 610106,China)

机构地区：[1]成都大学四川抗菌素工业研究所,成都610052 [2]成都大学医学院,成都610106 [3]成都中医药大学药学院,成都611137 [4]成都大学药学与生物工程学院农业部杂粮加工重点实验室,成都610106

出　　处：《中国药房》2019年第11期1459-1464,共6页China Pharmacy

基　　金：国家自然科学基金青年科学基金资助项目(No.81603288);四川省教育厅高校科研创新团队项目(No.17TD0010);四川省高校重点实验室开放基金立项项目(No.10Y201703)

摘　　要：目的:制备具有Ⅰ相代谢调控作用的葛根素微乳(R-PR-ME),并研究其在大鼠体内的药动学特征。方法:采用Shah法制备R-PR-ME和无代谢调控作用的葛根素微乳(NR-PR-ME),采用伪三元相图及以载药量为指标优化微乳处方,并用激光粒度仪对其粒径和多分散系数(PDI)进行表征。以大鼠为动物模型,采用高效液相色谱法,分别测定以葛根素计120 mg/kg的剂量灌胃R-PR-ME、NR-PR-ME和葛根素混悬液(PR-SP)前和灌胃后5、10、15、20、30、45、60、90、120、180、240、360、480、600min葛根素的血药浓度,使用DAS2.0软件计算药动学参数,SPSS19.0软件进行统计分析,以NR-PR-ME为参比制剂计算R-PR-ME的相对生物利用度。结果:R-PR-ME处方为油酸聚乙二醇甘油酯(油相)-聚山梨酯20(乳化剂)-辛酸癸酸聚乙二醇甘油酯(助乳化剂)的质量比为2∶4∶4,载药量为67.50mg/g,粒径为(22.59±0.53)nm(n=3),PDI为0.182±0.017(n=3);NR-PR-ME处方为大豆油(油相)-聚山梨酯80(乳化剂)-甘油(助乳化剂)的质量比1∶4.5∶4.5,载药量为61.32mg/g,粒径为(15.45±1.06)nm(n=3),PDI为0.156±0.012(n=3)。R-PR-ME、NR-PR-ME和PR-SP在大鼠体内的AUC0-600 min分别为(134.187±37.152)、(65.145±18.762)、(49.623±12.143) g min/mL;cmax分别为(1.316±0.306)、(1.082±0.294)、(0.425±0.106) g/mL;MRT分别为(155.068±33.204)、(100.264±27.683)、(60.524±14.086)min,t1/2β分别为(365.880±101.250)、(283.280±80.940)、(80.063±21.189)min(n=6);与PR-SP比较,R-PR-ME和NR-PR-ME的AUC0-600 min、cmax、MRT、t1/2β均明显增加(P<0.05或P<0.01);与NR-PR-ME比较,R-PR-ME的AUC0-600 min、MRT、t1/2β均更高(P<0.05),R-PR-ME的相对生物利用度为205.98%。结论:成功制得R-PR-ME,且其载药量高,与PR-SP和NR-PR-ME比较,R-PR-ME可显著增加葛根素在大鼠体内的生物利用度。OBJECTIVE:To prepare puerarin microemulsion with phase Ⅰ metabolic regulation (R-PR-ME) and to study pharmacokinetic characteristics of rats in vivo. METHODS:R-PR-ME and Puerarin microemulsion without metabolic regulation (NR-PR-ME)were prepared by Shah method. Pseudo-ternary phase diagram was used to optimize microemulsion formula using drug loading amount as index. The particle size and PDI of microemulsion were characterized by using a laser particle size analyzer. Rats were used as animal models,and HPLC method was used to determine the blood concentration of puerarin before and 5,10, 15,20,30,45,60,90,120,180,240,360,480,600 min after intragastric administration of R-PR-ME,NR-PR-ME and puerarin suspension(PR-SP)at puerarin dosage of 120 mg/kg. The pharmacokinetic parameters were calculated by using DAS 2.0 software. SPSS 19.0 software was used for statistical analysis. The relative bioavailability of R-PR-ME was calculated with NR-PR-ME as reference preparation. RESULTS:The formula of R-PR-ME included that oleoyl polyoxyl-6 glyserides (oil phase)-polysorbate 20 (emulsifier)-glycerides (co-emulsifier) mass ratio of 2 ∶ 4 ∶ 4;drug-loading amount of 67.50 mg/g, particle size was (22.59 ± 0.53) nm (n=3) and PDI was 0.182 ± 0.017 (n=3). The formula of NR-PR-ME included that soybean oil (oil phase)-polysorbate 80 (emulsifier)-glycerol(co-emulsifier)mass ratio of 1 ∶ 4.5 ∶ 4.5,drug-loading amount of 61.32 mg/g,particle size of(15.45±1.06)nm(n=3) and PDI of 0.156±0.012(n=3). Pharmacokinetic parameters of R-PR-ME,NR-PR-ME and PR-SP included that AUC0-600 min were (134.187±37.152),(65.145±18.762)and(49.623±12.143)μg·min/mL;cmax were(1.316±0.306),(1.082±0.294)and(0.425± 0.106)μ g/mL;MRT were(155.068 ± 33.204),(100.264 ± 27.683),(60.524 ± 14.086)min;t1/2 β were(365.880 ± 101.250),(283.280 ± 80.940),(80.063 ± 21.189) min (n=6),respectively. Compared with PR-SP,AUC0-600 min,cmax,MRT and t1/2 β of R-PR-ME and NR-PR-ME were increased significantly(P<0.05 or P<0.01). Compared with NR-PR-ME,AUC0

关 键 词：Ⅰ相代谢调控 葛根素微乳 药动学 生物利用度 大鼠 

分 类 号：R943[医药卫生—药剂学] R969.1[医药卫生—药学]