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|Issue Date: ||2005|
|Abstract: ||植入型药物释放系统（Implantable Drug Delivery Systems，以下简称IDDS）为一类经手术植入皮下或经穿刺导入体内的长期控释药剂。以可生物降解温敏水凝胶为技术平台的新型植入剂，可通过注射方式直接植入患处，并能生物降解，避免了传统植入型给药系统由于使用时需手术植入或取出的弊端；但解决这类凝胶因其网络结构疏松而造成药物释放速度过快，又成为一项新的课题。本论文以壳聚糖/甘油磷酸盐水溶胶为研究对象，通过化学交联和物理贯穿网络交联共同作用来提高凝胶网络密度、改善凝胶结构、增加凝胶强度从而提高凝胶稳定性及对药物的控缓释能力。本文首先研究并优化了交联强化温敏水溶胶的制备过程；通过粘度跟踪法描述溶胶-凝胶的相转变过程的影响因素和控制手段；采用Zeta电位分析、傅立叶红外检测、示差扫描量热法检测及扫描电镜等方法分析了溶胶电荷性质和凝胶内部结构，初步分析了体系内主要影响因素和相变机理；在上述研究基础上，分别以小分子药物氟尿嘧啶、生物大分子溶菌酶和荧光标记右旋糖酐为模型药物考察了该体系对药物的体外释放性质。研究结果表明，一定范围内，随着聚合物浓度、化学交联程度和/或甘油磷酸盐浓度的升高，体系相变过程加快、药物释放速度降低、水凝胶孔洞和结合水含量下降；这些因素的优化结果分别为：壳聚糖浓度2.0％，PVA浓度1.0％，交联剂浓度80mol/L，甘油磷酸盐4％。该配方的水溶胶在体温环境下3～5min形成凝胶；壳聚糖被化学交联形成Schiff’s 键；凝胶具有良好的机械强度和完整的结构；气相色谱检测不到戊二醛残留；体外释放实验结果说明，化学交联和贯穿网络能降低某些药物，特别是大分子药物的扩散速度，减小突释效应，达到药物控释的目的。|
Implantable Drug Delivery Systems (IDDS) which requires surgical parenteral implant could maintain a long-term steady release of drug to the specific site. Biodegradable thermosensitive hydrogel is potentially a novel in situ implant, which can be directly injected into body and biodegraded automatically without any surgical implant or taken-out. However, this high water content hydrogel is of loose structure and thus results in burst release of drugs, which becomes a major obstacle towards its clinical application.In this study the physical properties and drug delivery profile of a crosslinked chitosan/glycerophosphate (GP) thermosensitive hydrogel were investigated. Covalently crosslink and interpenetrating physical crosslink were both used to increase the gel density, to optimize the gel structure and to improve gel mechanical properties. They jointly contribute to the stability of hydrogel and a sustained delivery of drugs. The major influential factors to the preparation and gelation properties were investigated and an optimized result was obtained. Zeta potential analysis, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimeter (DSC) and Scanning Electron Microscopy (SEM) were used to analyze electrostatic properties and probe the hydrogel structure. Primary discussions on the gelation mechanisms were derived according to these results. Finally, fluorouracil, lysozyme and fluorescent isothiocyanate dextran were used as model drugs to evaluate the in vitro release profiles of the crosslink-intensified hydrogel.It can be concluded that with the increase of polymer concentration, crosslink density, and/or glycerophosphate concentration, the gelation rate is increased while the pore size decreased and the rate of drug release is reduced. The optimized composition of the thermosensive chitosan solution are listed as follows: 2%(w/w) chitosan, 1% (w/w) poly (vinyl alcohol)(PVA), 80mol/L crosslinker and 4% (w/w) glycerophosphate, which allow gelation upon heating to 37℃ within 3~5 min. FTIR test convinced that chitosan is covalently crosslinked by the formation of Schiff’s base. DSC and SEM results revealed the integrate hydrogel structure and improved mechanical properties with covalent crosslink and the addition of PVA. Gas chromatography test confirmed that no residual crosslinker was detected; ensuring therapeutic safeties of the hydrogel. The in vitro release profiles of the model drugs show that covalent crosslink and interpenetrate polymer networks (IPN) could distinctly decrease initial release and the average drug release rate, especially for the macromolecules. These results indicate that the crosslink-intensified hydrogel with good mechanical properties could achieve safe, effective and sustained delivery of drugs.
|Source URI: ||http://oaps.lib.tsinghua.edu.cn/handle/123456789/140|
|Source Fulltext: ||http://oaps.lib.tsinghua.edu.cn/bitstream/123456789/140/1/034%e9%99%88%e6%ac%a2%e6%ac%a22001012117.pdf|
|Appears in Collections:||Outstanding Thesis of Undergraduate Students 本科生优秀毕业论文（2005）|
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