姜黄素论文：姜黄素PLGA-PEG-PLGA载药胶束的研究.doc

姜黄素论文：姜黄素PLGA-PEG-PLGA载药胶束的研究【中文摘要】姜黄素(Curcumin, CUR)为黄色双酚类化合物,具有抗肿瘤、抗炎、抗病毒、抗氧化等多种药理作用。但其水溶性差,性质不稳定,体内代谢迅速,生物利用度低,严重制约了其开发与应用。如何改善CUR的各方面缺点,制备生物利用度高、用药量低的CUR制剂已经成为近年来药学工作者亟待解决的课题。由疏水-亲水链段组成的两亲性嵌段共聚物可以在水溶液中自发组装形成具有核-壳结构的超分子有序聚集体胶束,处于壳层的亲水链段可避免药物与水环境的接触,稳定聚合物胶束,避免体内网状内皮系统识别；疏水链段组成的内核提供了疏水微环境,可增加难溶性物质在水环境中的溶解度。该类胶束可提高脂溶性药物的水溶性,改善药物释放特性,实现药物靶向控制释放。本文首先进行了PLGA-PEG-PLGA嵌段共聚物的合成、结构表征等研究。在此基础上,研究了PLGA-PEG-PLGA包载CUR胶束的制备工艺、含量测定方法等,并测定了该嵌段共聚物的临界胶束浓度、空白和载药胶束的粒径分布、载药胶束的zeta电位和微观形态以及体外释药行为。同时,建立了血浆及各组织中CUR提取与定量分析的HPLC方法,研究了CUR载药胶束体内药动学性质及组织分布。研究发现,采用水透析方法制备CUR的PLGA-PEG-PLGA胶束,其包封率平均值为70.030.34%,载药量平均值为6.40.02%,平均粒径为26.29nm,计算药物的溶解度为1.47mg/ml, zeta电位为-0.7lmV。体外释放研究表明,CUR胶束的体外释放呈现先突释后缓释的特性,符合双相双指数动力学模型。体内药动学研究表明,CUR胶束的药时曲线下面积、平均滞留时间、清除半衰期和分布半衰期均高于对照制剂,分别为对照制剂的1.31倍、2.67倍、2.48倍和4.54倍。同时,也降低了CUR血浆总清除率和峰浓度。半衰期、平均滞留时间的延长以及总清除率的降低,提示该胶束可延长CUR体内作用时间。组织分布研究发现,与CUR对照制剂相比,CUR胶束在脑、肺的Ce值分别为2.00和1.02；相对摄取率(Relative uptake efficiency,RUE)分别为14.31、5.56；相对靶向率(Relative targeting efficiency,RTE)分别为247.22%和34.72%，表明该胶束可明显促进CUR在脑和肺部的分布和富集。【英文摘要】Curcumin is a yellow colored polyphenol with anticancer, anti-inflammatory, anti-virus and antioxidant activities. Its low water solubility, unstablity, quick metabolism and lower bioavailability limited its development and usage. So, how to overcome its shortcoming and improve curcumins bioavailability and reduce its dosage has been an urgent problem to resolve for researchers.Amphipathic copolymer composed of hydrophilic and hydrophobic segment can self-assemble to form micelle with core-shell structure. Hydrophilic chain segment can prevent the touch of drug and water, stabilize copolymer micelle and avoid identification of reticuloendothilial system in body. Hydrophobic segment can provide hydrophobic microenviroment to increase the solubility of water insoluble drug in water. This micelle is able to raise drugs water-solubility, improve release property and obtain drugs target controlled-release.PLGA-PEG-PLGA block-copolymer was synthesized by ring-openning polymerization of PEG, lactide and glycolide with stannous ocatate as catalyst, and its structure was characterized. Then, preparation process and quantitative analysis of curcumin-loaded micelle were studied, and block-copolymers CMC, particle diameter distribution of blank and drug-loaded micelle and Zeta potential, micromophology and in vitro release behavior of drug-loaded micelle were also determined. CURs extracion from plama and tissues in mice and HPLC quantitative methodology were constructed, and in vivo pharmacokinetics and distributions of curcumin in tissues were researched. The results demonstrated that mean entrapment efficiency, mean drug-loading rate, mean particle parameter, solubility in water and zeta potential of CUR-loaded micelle prepared by water dialysis were 70.030.34%,6.40.02%,26.29nm, 1.47mg/ml and-0.71mV, respectively. The in vitro release showed that the release of CUR from micelle was in line with ambiexponent and biphasic kinetics equation, showing property of burst release earlier followed slow release.In vivo pharmacokenetics study showed that area under drug-time curve, mean retention time (MRT), elimination half-time and distribution half-time were 1.31 fold,2.67 fold,2.48 fold and 4.54 fold these of the control formulation, respectively. Additionally, plasma total body clearance and peak concentration were also decreased. The prolongation of MRT and decrease of total body clearance hinted that CUR-loaded micelle could lengthen curcumins action time in vivo.The study on tissue distribution in vivo indicated that Ce, RUE and RTE for brain and lung were 2.00 and 1.02,14.31 and 5.56, and 247.22% and 34.72%, respectively, showing that CUR-loaded micelle could obviously improve distribution and gathering of curcumin in brain and lung.【关键词】姜黄素 PLGA-PEG-PLGA胶束 体外释放 药动学 组织分布【英文关键词】curcumin PLGA-PEG-PLGA micelles in vitro release pharmacokinetics tissue distribution【目录】姜黄素PLGA-PEG-PLGA载药胶束的研究中文摘要10-12Abstract12-13符号说明14-15前言15-291. 结构、形态和组成15-162. 嵌段共聚物胶束的特点162.1 增溶作用162.2 靶向性162.3 延长作用时间163. 嵌段共聚物胶束的制备16-183.1 直接溶解法16-173.2 透析法173.3 水包油乳化法173.4 溶剂挥发法173.5 盐析法173.6 溶液铸模法17-183.7 快速纳米沉淀法184. PEG嵌段共聚物胶束在抗癌药物中的应用18-214.1 增溶作用194.2 靶向性19-204.3 控制释放204.4 抗多药耐药性20-215 姜黄素及其制剂研究进展21-285.1 姜黄素的研究概况21-235.2 CUR制剂的研究23-286 立题依据28-29第一章 PLGA-PEG-PLGA的合成29-351 仪器及试剂29-301.1 仪器291.2 试剂29-302 实验部分30-342.1 试剂预处理302.2 PLGA-PEG-PLGA聚合物的合成30-312.3 PLGA-PEG-PLGA聚合物的表征31-343 本章小结34-35第二章 CUR载药胶束的制备、理化性质及体外释放研究35-521 仪器与试剂35-361.1 仪器351.2 试剂35-362 实验方法36-512.1 CUR含量分析方法的建立36-392.2 载药量及包封率的测定392.3 共聚物胶束的制备39-402.4 胶束形态、粒径及zeta电位测定40-462.5 聚合物临界胶束浓度(C