藤黄酸B聚乙二醇单甲醚化脂质体的制备及大鼠体内药动学的研究
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摘要
目的优化藤黄酸B(morellic acid B,MAB)聚乙二醇单甲醚(mPEG)化脂质体(MAB-mPEG-LPS)的制备工艺,并对其体外释放及大鼠体内药动学行为进行研究。方法建立藤黄酸B定量分析方法,以包封率、粒径分布作为考察指标,采用正交试验设计优化MAB-mPEG-LPS处方,得到MAB-mPEG-LPS包封率最高的制备工艺;采用透射电镜下观察MAB-mPEG-LPS表面形态,考察MAB-mPEG-LPS在60 d内的稳定性,采用透析法对MAB-mPEG-LPS体外释放行为进行研究,雄性SD大鼠尾静脉分别注射1.50 mg/kg的MAB、MAB脂质体(MAB-LPS)、MAB-mPEG-LPS,比较MAB、MAB-LPS、MAB-mPEG-LPS药动学行为。结果正交试验优化后MAB-mPEG-LPS的最优处方为氢化大豆卵磷脂(HSPC)128 mg,mPEG的用量为10 mg,HSPC-胆固醇(CH)质量比8∶1,MAB-mPEG-LPS包封率达到83.21%,MAB-mPEG-LPS外观表面光滑,粒径均匀;体外释放结果表明MAB-mPEG-LPS具有缓释且长效作用,在60 d内储存稳定;MAB-mPEG-LPS中MAB在大鼠体内t1/2β为66.925 min,是MAB的4.43倍,是MAB-LPS的3.29倍;AUC0~∞为241.372 mg·min/L,是MAB在大鼠体内3.64倍,是MAB-LPS的1.99倍。结论 MAB-mPEG-LPS可延长MAB在大鼠体内的循环时间,增加体内AUC0~∞等特性。
Objective To optimize the preparation process of morellic acid B(MAB) mPEG liposomes(MAB-mPEG-LPS), and to study the in vitro release behavior and pharmacokinetics of MAB-mPEG-LPS in rats. Methods The analytical method of MAB was established; Encapsulation efficiency and particle size were used as the indexes to optimize the mPEG liposomes by orthogonal test, and the highest encapsulation efficiency of MAB-mPEG-LPS was obtained; Transmission electron microscope was used to observe the surface morphology of MAB-mPEG-LPS, and the stability of MAB-mPEG-LPS was measured in 60 d. Dialysis method was also adopted to study the MAB-mPEG-LPS release in vitro; Male SD rats were injected with MAB(1.50 mg/kg), MAB-LPS(1.50 mg/kg), MAB-mPEG-LPS(1.50 mg/kg) via tail vein, and differences in pharmacokinetics parameters of MAB, MAB-LPS, and MABmPEG-LPS were compared. Results The optimized formula of MAB-mPEG-LPS: HSPC was 128 mg, mPEG was 10 mg, HSPC-CHOL was 8∶1. Encapsulation efficiency of MAB-mPEG-LPS was 83.21%. MAB-mPEG-LPS had uniform particle size and smooth surface; In vitro release results showed that the MAB-mPEG-LPS had slow release and long-term effect. It was stable in 60 d; In vivo study showed that t_(1/2β) of MAB in MAB-mPEG-LPS was 66.925 min, which was 4.43 fold to MAB. MAB-mPEG-LPS was 3.29 fold to MA-LPS; AUC0-∞ of MAB in MAB-mPEG-LPS was 241.372 mg·min/L, which was 3.64 fold to MAB. MAB-mPEG-LPS was 1.99 fold to MAB-LPS. Conclusion MAB-mPEG-LPS could prolong the circulation time and increase AUC0-∞ of MAB in rats.
Objective To optimize the preparation process of morellic acid B(MAB) mPEG liposomes(MAB-mPEG-LPS), and to study the in vitro release behavior and pharmacokinetics of MAB-mPEG-LPS in rats. Methods The analytical method of MAB was established; Encapsulation efficiency and particle size were used as the indexes to optimize the mPEG liposomes by orthogonal test, and the highest encapsulation efficiency of MAB-mPEG-LPS was obtained; Transmission electron microscope was used to observe the surface morphology of MAB-mPEG-LPS, and the stability of MAB-mPEG-LPS was measured in 60 d. Dialysis method was also adopted to study the MAB-mPEG-LPS release in vitro; Male SD rats were injected with MAB(1.50 mg/kg), MAB-LPS(1.50 mg/kg), MAB-mPEG-LPS(1.50 mg/kg) via tail vein, and differences in pharmacokinetics parameters of MAB, MAB-LPS, and MABmPEG-LPS were compared. Results The optimized formula of MAB-mPEG-LPS: HSPC was 128 mg, mPEG was 10 mg, HSPC-CHOL was 8∶1. Encapsulation efficiency of MAB-mPEG-LPS was 83.21%. MAB-mPEG-LPS had uniform particle size and smooth surface; In vitro release results showed that the MAB-mPEG-LPS had slow release and long-term effect. It was stable in 60 d; In vivo study showed that t_(1/2β) of MAB in MAB-mPEG-LPS was 66.925 min, which was 4.43 fold to MAB. MAB-mPEG-LPS was 3.29 fold to MA-LPS; AUC0-∞ of MAB in MAB-mPEG-LPS was 241.372 mg·min/L, which was 3.64 fold to MAB. MAB-mPEG-LPS was 1.99 fold to MAB-LPS. Conclusion MAB-mPEG-LPS could prolong the circulation time and increase AUC0-∞ of MAB in rats.
引文
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[21]刘迪,杨红,吕小燕,等.载碳菁类染料泡囊的制备和表征及其光热效应研究[J].中国新药杂志,2016,25(11):1275-1280.
[22]黄天擎,何瑞曦,陈贺骏涛,等.丹皮酚泡囊乳膏的制备及其体外透皮吸收考察[J].安徽中医药大学学报,2016,35(3):79-83.
[23]何瑞曦.丹皮酚聚乙二醇化非离子表面活性剂泡囊的制备、表征、及其初步药动—药效学研究[D].合肥:安徽中医药大学,2016.
[24]张海燕,齐云,廖永红,等.注射剂常用增溶性药用辅料的安全与增溶研究[J].中国实验方剂学杂志,2011,17(11):1-4.
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[26]陆丽华,李芸芸,纪丹妮,等.聚乙二醇电解质散剂用于术前肠道准备的安全性与有效性[J].护士进修杂志,2010,25(5):427-428.
[27]梁博,孙璐,孙树东,等.聚乙二醇刷型聚合物在聚砜膜上的光化接枝[J].高分子材料科学与工程,2008,24(10):163-166.
[28]张璇,潘仕荣,吕澍,等.聚乙二醇-聚乙烯亚胺共聚物的制备及其表征[J].中山大学学报:自然科学版,2006,45(6):53-57.
[29]李睿.新藤黄酸m PEG化脂质体的制备、大鼠体内药动学参数及体外抑制Hep G2细胞活性研究[D].合肥:安徽中医药大学,2016.
[30]袁松,孙会敏,丁丽霞.脂质体物理化学稳定性研究进展[J].中国药事,2011,25(4):384-388.
[31]黄兴亮.达托霉素长循环脂质体抗耐甲氧西林金葡菌的研究[D].重庆:西南大学,2014.
[32]丁倩,李寒梅,孙逊.环巴胺固体脂质纳米粒的研究[J].华西药学杂志,2017,32(1):9-12.
[2]吕磊,袁敬东,黄韬,等.藤黄酸对膀胱癌BIU-87细胞侵袭及迁移能力的影响[J].时珍国医国药,2016,27(10):2369-2371.
[3]陆莹,李庆林.新藤黄酸诱导黑色素瘤B16细胞线粒体自噬的机制研究[J].现代中西医结合杂志,2016,25(19):2079-2082.
[4]黄霞,朱婷婷,罗晴,等.新藤黄酸纳米脂质载体制备及其药剂学性质研究[J].中草药,2013,44(11):1400-1406.
[5]Han Q B,Wang Y L,Yang L,et al.Cytotoxic polyprenylated xanthones from the resin of Garcinia hanburyi[J].Chem Pharm Bull,2006,54(2):265-267.
[6]Sukpondma Y,Rukachaisirikul V,Phongpaichit S.Antibacterial caged-tetraprenylated xanthones from the fruits of Garcinia hanburyi[J].Chem Pharm Bull,2005,53(7):850-852.
[7]贾步云.藤黄酸B分离纯化、纳米脂质载体制备及初步药效学研究[D].合肥:安徽中医药大学,2015.
[8]贾步云,彭代银,李珊珊,等.藤黄中MA的制备分离方法优选及结构确证[J].安徽中医药大学学报,2015,34(1):77-81.
[9]黄霞,罗晴,朱婷婷,等.新藤黄酸固体脂质纳米粒在大鼠体内药物代谢动力学研究[J].安徽中医学院学报,2013,32(3):68-71.
[10]林雅铃,张安强,王炼石.磷酸川芎嗪星型聚乳酸缓释微球的制备与体外释放研究[J].中草药,2010,41(10):1627-1631.
[11]Lin T,Fang Q,Peng D,et al.PEG ylated non-ionic surfactant vesicles as drug delivery systems for gambogenic acid[J].Drug Deliv,2013,20(7):277-284.
[12]丁倩,李寒梅,孙逊.环巴胺固体脂质纳米粒的研究[J].华西药学杂志,2017,32(1):9-12.
[13]管庆霞,王利萍,刘振强,等.马钱子碱固体脂质纳米粒的细胞毒性及细胞摄取试验[J].中国实验方剂学杂志,2017,23(5):1-6.
[14]王晶.叶酸偶联聚合物修饰的紫杉醇纳米脂质载体制备及性质研究[J].辽宁中医药大学学报,2017,19(5):1-4.
[15]黄瑞,郭盼,刘勃缨,等.藤黄酸纳米结构脂质载体的制备及抗肿瘤作用初步评价[J].天津中医药,2017,34(1):62-65.
[16]代文婷,陈进,何争民,等.脱甲氧基姜黄素纳米脂质载体冻干工艺的优化[J].现代医药卫生,2017,33(1):27-29.
[17]薛雨晨,苏菊,姜丰,等.灯盏花乙素缓释微球的制备及药剂学性能考察[J].中国实验方剂学杂志,2017,23(6):7-12
[18]冯超,王群星,熊雪丰,等.延胡索乙素胃漂浮缓释微球的制备[J].中成药,2017,39(2):291-296.
[19]崔青,赵红,张长桥,等.壳聚糖功能微球负载贵金属的研究进展[J].化工进展,2017,36(2):595-601.
[20]殷启风,杨鹏,王玉娟,等.新型羧甲基壳聚糖包裹C-藻蓝蛋白负载CD59配体的靶向纳米微球的制备及其对He La细胞的杀伤作用[J].中国肿瘤生物治疗杂志,2017,24(2):1-7.
[21]刘迪,杨红,吕小燕,等.载碳菁类染料泡囊的制备和表征及其光热效应研究[J].中国新药杂志,2016,25(11):1275-1280.
[22]黄天擎,何瑞曦,陈贺骏涛,等.丹皮酚泡囊乳膏的制备及其体外透皮吸收考察[J].安徽中医药大学学报,2016,35(3):79-83.
[23]何瑞曦.丹皮酚聚乙二醇化非离子表面活性剂泡囊的制备、表征、及其初步药动—药效学研究[D].合肥:安徽中医药大学,2016.
[24]张海燕,齐云,廖永红,等.注射剂常用增溶性药用辅料的安全与增溶研究[J].中国实验方剂学杂志,2011,17(11):1-4.
[25]Harris J M,Hundley N H,Shannon T G,et al.Polyethylene glycols as soluble,recoverable,phase-transfer catalysts[J].JAMA,1982,47(24):4789-4791.
[26]陆丽华,李芸芸,纪丹妮,等.聚乙二醇电解质散剂用于术前肠道准备的安全性与有效性[J].护士进修杂志,2010,25(5):427-428.
[27]梁博,孙璐,孙树东,等.聚乙二醇刷型聚合物在聚砜膜上的光化接枝[J].高分子材料科学与工程,2008,24(10):163-166.
[28]张璇,潘仕荣,吕澍,等.聚乙二醇-聚乙烯亚胺共聚物的制备及其表征[J].中山大学学报:自然科学版,2006,45(6):53-57.
[29]李睿.新藤黄酸m PEG化脂质体的制备、大鼠体内药动学参数及体外抑制Hep G2细胞活性研究[D].合肥:安徽中医药大学,2016.
[30]袁松,孙会敏,丁丽霞.脂质体物理化学稳定性研究进展[J].中国药事,2011,25(4):384-388.
[31]黄兴亮.达托霉素长循环脂质体抗耐甲氧西林金葡菌的研究[D].重庆:西南大学,2014.
[32]丁倩,李寒梅,孙逊.环巴胺固体脂质纳米粒的研究[J].华西药学杂志,2017,32(1):9-12.