【作者】 刘志东；

【导师】 潘卫三；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2006， 博士

【摘要】 眼部药物传递作为控制释放领域的重要分支近二十年来备受人们的关注。眼睛的有效保护机制与高度敏感性促使人们探索开发安全合理的给药系统，同时又限制了许多药剂学手段的应用，为此类剂型的设计带来了极大的困难。本文分别以依诺沙星（ENX）和加替沙星（GAT）为模型药物，设计了两种新型眼用制剂—ENX眼用缓释凝胶剂及离子敏感型的GAT在体（in situ）眼用凝胶剂，对其处方组成、制备工艺、眼部刺激性和眼部代谢动力学进行较为全面的研究和评价。具体内容包括以下6部分： 1、基本理化性质的研究 研究结果表明：ENX和GAT眼部吸收的主要屏障是角膜上皮细胞层，提示为增加药物的角膜透过率(P_app)，需要选用适宜的渗透促进剂。 2、依诺沙星眼用缓释凝胶剂的研究 ①家兔离体角膜透过试验结果表明：1％的泊洛沙姆F68和2％羟丙基—β—环糊精（HP-β-CD）分别使ENX的表观渗透系数增加1.65和2.05倍，与对照组呈现显著性差异（p＜0.01）；金属离子络合剂EDTA与水溶性月桂氮卓酮（Azone）在本文实验条件下未能显著增大ENX的P_app（p＞0.05）；所有渗透促进剂均未显著改变ENX透过角膜的滞后时间；深入研究HP-β-CD浓度与ENX角膜透过性关系的实验结果表明，随着HP-β-CD浓度增加（2％、4％、6％、8％和12％），ENX的P_app先增大后减小，2％、4％和6％HP-β-CD组ENX的P_app与对照组相比显著性增加（P＜0.01），4％的HP-β-CD使得ENX的P_app达到最大，是对照组的3.58倍；8％和12％的HP-β-CD组ENX的P_app与对照组相比没有显著性差异（P＞0.05）；提示HP-β-CD作为一种安全有效的渗透促进剂有望在实践中获得应用。 ②体外溶出度试验结果表明，以3％的HPMC K4M和F4M为基质制备的ENX凝胶剂的体外释放行为符合眼用缓释制剂的要求；体外释放度影响因素试验结果表明，释放面积对释放度有显著性影响，pH值和转速略有影响，而扩散屏障没有影响；离体角膜透过实验结果表明，以F4M为基质制备的凝胶剂中ENX的表观渗透系数(P_app)是对照组（滴眼液）的1.34倍，说明F4M与眼角膜的相容性较好，是一种理想的眼用制剂增稠剂，可以在眼用制剂中广泛采用。 3、离子敏感型加替沙星眼用在体凝胶剂的研究更多还原

【Abstract】 As one of the important fields of controlled release, ophthalmic drug delivery has received extensive interests during the last two decades. The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed, however, the applications of numerous pharmaceutical methods are limited simultaneously, which presents great challenge in designing ophthalmic dosage forms. In this dissertation, enoxacin （ENX） and gatifloxacin （GAT） were selected as model drugs, then an ophthalmic sustain-released gel of ENX and an ion-activated in situ gelling ophthalmic drug delivery system for GAT were developed and evaluated in vitro and in vivo, respectively. Seven main sections were included in this paper:1、 The study on the solubilities and partition coefficients of drugsThe results showed that the solubilities of ENX and GAT were both dependent on pH value, and the partition coefficients were relatively low, which suggested the rate-limiting barrier was corneal epithelium. In order to increase the transcorneal influx of both drugs, penetration enhancers were needed to employ.2、 The study on ophthalmic sustain-released gel of ENX? The permeability of ENX across isolated rabbit cornea was measured using in vitro method under various penetration enhancers. The diffusion behaviors of ENX across isolated rabbit cornea possessed zero-order kinetic characteristic. An apparent permeation coefficient of 1.795×10^-6 cm·s^-1 was found without enhancers. 1% poloxamer （F68） and 2% HP-β-CD improved the apparent permeability of ENX as much as 1.65 and 2.05, respectively. However, 0.05%Azone and 0.5%EDTA did not improve the apparent permeability of ENX. When the concentrations of HP-β-CD varied from 2% to 4%, the apparent permeation coefficient of ENX was increased 2.58-fold, but further increasing HP-β-CD concentration to 12% led to lower the P_app value of ENX. All enhancers did not significantly change the transcorneal lag time of ENX. The irritancy of poloxamer and Azone was observed.? The results of in vitro release studies showed that the ENX gel based 3% HPMC K4M and 3%HPMC F4M povided sustained release of the drug over an 8-h period in vitro.Diffusion area has significantly effect on drug release, and pH value of medium and rotation rate have effcet on drug release.However, the diffusion shield has no effect on drug release. The P_app value of the preparation based on 3% HPMC F4M was 1.34-fold of conventional eye drops of ENX. The results suggested that the compatibility between the更多还原