基于Ⅰ相代谢调控的葛根素微乳的制备及其药动学研究
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篇名: 基于Ⅰ相代谢调控的葛根素微乳的制备及其药动学研究
TITLE:
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、600 min葛根素的血药浓度,使用DAS 2.0软件计算药动学参数,SPSS 19.0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67.50 mg/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61.32 mg/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) μg·min/mL;cmax分别为(1.316±0.306)、(1.082±0.294)、(0.425±0.106) μg/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。
ABSTRACT: 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) μg/mL; MRT were (155.068±33.204), (100.264±27.683), (60.524±14.086) min; t1/2β 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 t1/2β of R-PR-ME and NR-PR-ME were increased significantly (P<0.05 or P<0.01). Compared with NR-PR-ME, AUC0-600 min, MRT and  t1/2β of R-PR-ME were more higher (P<0.05). The relative bioavailability of of R-PR-ME was 205.98%. CONCLUSIONS: R-PR-ME is prepared successfully with high drug-loading amount, and can significantly increase the bioavailability of puerarin in rats, compared with PR-SP and NR-PR-ME.
期刊: 2019年第30卷第11期
作者: 代丽萍,李维,卓虹伊,刘贵容,贺艳,胡一晨,宋雨,邹亮
AUTHORS: DAI Liping,LI Wei,ZHUO Hongyi,LIU Guirong,HE Yan,HU Yichen,SONG Yu,ZOU Liang
关键字: Ⅰ相代谢调控;葛根素微乳;药动学;生物利用度;大鼠
KEYWORDS: Phase Ⅰ metabolism regulation; Puerarin microemulsion; Pharmacokinetics; Bioavailability; Rat
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