穿心莲超分子提取物的胶束给药系统研究
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摘要
穿心莲是一种常用的清热解毒类中草药,现代研究表明,穿心莲具有显著的抗肿瘤作用,其有效成分是以穿心莲内酯、脱水穿心莲内酯、14-去氧穿心莲内酯为代表的二萜内酯类化合物。穿心莲内酯和脱水穿心莲内酯在2010版中国药典中是穿心莲药材及其制剂含量测定的重要指标。韩光等采用超分子技术富集穿心莲醇提物,得到的穿心莲超分子提取物中二萜内酯类成分的含量达到50%以上,具有显著的体内抗肿瘤作用,且明显优于穿心莲内酯单体及穿心莲乙醇粗提物。
为提高穿心莲超分子提取物在水中的溶解度,本课题采用现代靶向制剂技术,以泊洛沙姆188为载体材料,将穿心莲超分子提取物制备成胶束给药系统。制备方法采用薄膜分散法,以包封率、载药量为主要指标,考察投药量、水化体积、旋转蒸发温度、水相pH值等影响因素,选择影响较大的三个因素,即投药量、水化体积、旋转蒸发温度进行正交设计,得到最优处方为:投药量15mg,ploxamer 188 120mg,水化体积8mL。优化得到的胶束溶液均一澄明,平均粒径为190nm。包封率为(85.7+2.1)%,载药量(3.9±0.1)%。以超分子提取物溶液为对照,胶束的释放实验结果显示其具有一定的缓释效果。
以超分子提取物的PEG溶液为对照组,穿心莲超分子提取物胶束为样品,小鼠尾静脉注射后,不同时间测定小鼠组织中穿心莲内酯、脱水穿心莲内酯的浓度,并与原药对比,评价组织分布特点。结果显示与对照组相比,胶束在血液中的浓度降低,在组织器官中的浓度相对增加,其中肝脏、肺部的浓度相对增加较为显著。提示胶束有利于肝、肺部的抗肿瘤治疗。结果表明poloxamer188胶束可作为难溶性药物载体,提高在特定组织中的靶向性。
Andrographis is one of commonly used cleaning heat and detoxificating Chinese herbal medicine. Modern research shows that Andrographis has significant anti-tumor effect. It’s major active ingredient is andrographolide,dehydroandrographolide and 14-deoxyandrographolide. andrographolide and dehydroandrographolide are important indicators of the quality inspection in the 2010 edition Chinese Pharmacopoeia.By using supermolecule techniques to enrich ethanol extract of Andrographis paniculata, Han Guang obtained supramolecular extract of Andrographis (SEA), which contained more than 50% of andrographolides.
The topic was based on SEA to prepare micelles,which used modern targeting drug delivery system technology,and took poloxamer 188 as carrier material. The SEA-loaded micelles were prepared by thin-film hydration method.The entrapment efficiency was taken as the index to evaluate the effects of the amount of SEA,volume of water phase,temperature of rotary evaporation,and pH of water phase on the characteristics of micelles.Chosing the most influential three factors: the amount of SEA,volume of water phase,temperature of rotary evaporation,to design Orthogonal experiment, the final optimized formulation was 15mg of Andrographis supramolecular extract,120mg ploxamer 188 and 8mL of water phase.The optimized supramolecular micelles solution was uniform and clear : arerage particle size was 198nm;entrapment efficiency was (85.7±2.1)% ;drug loading was (3.9±0.1)% . Compared with SEA solution,in vitro release results of SEA-loaded micelles indicated that the drug release slowly from micelles.
Using the original extract as the control group, giving tail vein injection, measuring the concentration of andrographolide and dehydroandrographolide in the organization at different time an d comparing it with the original drug to evaluate the tissue distribution characteristics. The results showed that the relative increase in the concentration of liver and lung was more significant compared with the PEG original drug, so it was beneficial to the treatment of liver cancer and lung cancer.The results showed that poloxamer188 micelle as the carrier of insoluble drugs can improve the targeting of specific tissues.
为提高穿心莲超分子提取物在水中的溶解度,本课题采用现代靶向制剂技术,以泊洛沙姆188为载体材料,将穿心莲超分子提取物制备成胶束给药系统。制备方法采用薄膜分散法,以包封率、载药量为主要指标,考察投药量、水化体积、旋转蒸发温度、水相pH值等影响因素,选择影响较大的三个因素,即投药量、水化体积、旋转蒸发温度进行正交设计,得到最优处方为:投药量15mg,ploxamer 188 120mg,水化体积8mL。优化得到的胶束溶液均一澄明,平均粒径为190nm。包封率为(85.7+2.1)%,载药量(3.9±0.1)%。以超分子提取物溶液为对照,胶束的释放实验结果显示其具有一定的缓释效果。
以超分子提取物的PEG溶液为对照组,穿心莲超分子提取物胶束为样品,小鼠尾静脉注射后,不同时间测定小鼠组织中穿心莲内酯、脱水穿心莲内酯的浓度,并与原药对比,评价组织分布特点。结果显示与对照组相比,胶束在血液中的浓度降低,在组织器官中的浓度相对增加,其中肝脏、肺部的浓度相对增加较为显著。提示胶束有利于肝、肺部的抗肿瘤治疗。结果表明poloxamer188胶束可作为难溶性药物载体,提高在特定组织中的靶向性。
Andrographis is one of commonly used cleaning heat and detoxificating Chinese herbal medicine. Modern research shows that Andrographis has significant anti-tumor effect. It’s major active ingredient is andrographolide,dehydroandrographolide and 14-deoxyandrographolide. andrographolide and dehydroandrographolide are important indicators of the quality inspection in the 2010 edition Chinese Pharmacopoeia.By using supermolecule techniques to enrich ethanol extract of Andrographis paniculata, Han Guang obtained supramolecular extract of Andrographis (SEA), which contained more than 50% of andrographolides.
The topic was based on SEA to prepare micelles,which used modern targeting drug delivery system technology,and took poloxamer 188 as carrier material. The SEA-loaded micelles were prepared by thin-film hydration method.The entrapment efficiency was taken as the index to evaluate the effects of the amount of SEA,volume of water phase,temperature of rotary evaporation,and pH of water phase on the characteristics of micelles.Chosing the most influential three factors: the amount of SEA,volume of water phase,temperature of rotary evaporation,to design Orthogonal experiment, the final optimized formulation was 15mg of Andrographis supramolecular extract,120mg ploxamer 188 and 8mL of water phase.The optimized supramolecular micelles solution was uniform and clear : arerage particle size was 198nm;entrapment efficiency was (85.7±2.1)% ;drug loading was (3.9±0.1)% . Compared with SEA solution,in vitro release results of SEA-loaded micelles indicated that the drug release slowly from micelles.
Using the original extract as the control group, giving tail vein injection, measuring the concentration of andrographolide and dehydroandrographolide in the organization at different time an d comparing it with the original drug to evaluate the tissue distribution characteristics. The results showed that the relative increase in the concentration of liver and lung was more significant compared with the PEG original drug, so it was beneficial to the treatment of liver cancer and lung cancer.The results showed that poloxamer188 micelle as the carrier of insoluble drugs can improve the targeting of specific tissues.
引文
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[2] Geethangili M, Rao YK, Fang SH, Tzeng YM. Cytotoxic constituents from Andrographis paniculata induce cell cycle arrest in Jurkatcells. Phytother Res 2008,22:1336–41.
[3] Zhou J, Lu GD, Ong CS, Ong CN, Shen HM. Andrographolidesensitizes cancer cells to TRAIL-induced apoptosis via p53-mediateddeath receptor 4 up-regulation. Mol Cancer Ther 2008;7:2170–80.
[4] Yang L, Wu D, Luo K, Wu S, Wu P. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrialpathway involving p53 participation in hepatocellular carcinoma(SMMC-7721) cells. Cancer Lett 2009,276:180–8.
[5] Liang FP, Lin CH, Kuo CD, Chao HP, Fu SL. Suppression of v-srctransformation by andrographolide via degradation of the v-srcprotein and attenuation of the Erk-signaling pathway. J BioChem 2008,283:5023–33.
[6]马廷升,宋思才等.正交实验优化穿心莲浸膏碱水生产工艺的研究[J].中国药师,2004,7(6):439-440
[7]卓菊,王小根.正交设计研究穿心莲中脱水穿心莲内酯提取工艺[J].中南药学,2005,3(3):30-32
[8]丁琤张勇林国卫等.微波辅助提取穿心莲内酯的研究[J].广东农业科学2011(11)20-22
[9]葛发欢,林秀仙等.超临界CO2流体萃取穿心莲有效成分的正交试验研究[J].中药材,2002,25(2):101-102
[10]范云鸽,张秀莉等.大孔吸附树脂提取穿心莲总内酯的研究[J].离子交换与吸附,2002,18(1):30-35
[11]韩光,许笑笑,许启泰.β-环糊精包合穿心莲有效成分的工艺研究[J].中草药,2007,38:159-161
[12]邵向群.扶正治则在恶性肿瘤治疗中的临床应用[J].中医文献杂志,2009,2(6):37-39
[13]陈培丰.清热解毒法在恶性肿瘤治疗中的意义和作用机制[J].浙江中医学院学报,2001,25(5):11-12.
[14]王宇岭,李道明,徐红等.康莱特注射液联合化疗治疗晚期非小细胞肺癌[J].癌症进展杂志,2005,3(3):274-275
[15]姜延波.康莱特注射液治疗原发性肝癌的临床观察[J].现代肿瘤医学,2006,14(4):485-486
[16]汪秋红,李金才.鸦胆子油提取制剂及临床应用[J].黑龙江医学,2002,26(10):762.
[17]汤涛,蒙凌华,陈陵际等.鸦胆子油乳具有多药耐药逆转和拓扑异构酶Ⅱ抑制作用[J].中国药理学通报,2001,17(5):534-539.
[18]李平祝,杨卓理等.多功能聚合物胶束的最新研究进展[J].中国新药杂志,2008,17(3):199-20
[19]张晓君,王东凯,韩晓.聚合物胶束作为药物传递系统的研究进展[J].中国药剂学杂志,2009,7(3):177-183.
[20]伍善广,杨帆等.药物胶束嵌段共聚合物的研究进展[J].现代食品与药品杂志,2007,17(2):14-17.
[21]姜维,王运东等.嵌段共聚物胶束作为药物载体的研究进展[J].中国医药工业杂志,2004,35(4):242-246.
[22]李珺婵,方晓玲.嵌段共聚物胶束作为抗肿瘤药物载体的研究进展[J].国外医学药学分册,2004,31(1):48-53.
[23]Vonarbourg A,Passirani C,Saulnier P,el a1.Parameters influencing the stealthiness of colloidal[J].Biomaterials,2006,27(24):4356-4373.
[24]Kataoka K,Matsumoto T,Yokoyama M,et a1.Doxorubicin-loaded poly(ethyleneglycol)-poly(beta-benzyl-L-aspartate) copolymer micelles:their pharmaceutical characteristics and biological significance[J].J Controlled Release,2000,64(1-3):143-153.
[25]Kim SY,Lee YM,Shin HJ,et a1.Indomethacin-loaded methoxy poly(ethyleneglycol)/poly(epsilon-caprolactone)diblock copolymeric nanosphere:pharmacokinetic characteristics of indomethacin in the normal Sprague-Dawley rats[J].Biomaterials,2001,22(14):2049-2056.
[26] Kumar N,Pavikumar MNV, Domb A J.Biodegradable block copolymers[J].Adv Drug Deliv Rev,2001,53(1):23-44.
[27]林宏英,吴建梅等.难溶性抗肿瘤药物载体—嵌段共聚物胶束[J].中草药,2006,37(4):481-485.
[28]Kataoka K,Matsumoto T,Yokoyama M,et al.Doxorubicin-loaded poly (ethylene glycol)-poly(β-benzyl-Laspartate) copolymer micelles: Their pharmaceutical characteristics and biological significance[J].J Control Release,2000,64(1-3):143-153.
[29]Allen C,Maysinger D,Eisenberg A.Nano-engineering block copolymer aggregates for drug delivery[J].Colloids Surf B:Biointerfaces,1999,16(1-4):3-27.
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