疏水结晶类药物巩膜表面缓释系统及其药代动力学优化和眼底病的治疗评估

Eye diseases at the ocular posterior segment such as uveitis and proliferative vitreoretinopathy are often chronic and refractory diseases which carry a high prevalence of blindness and a high epidemic profile in China. The key to treat and bring them under control is to maintain the-above-therapeutic drug level in the target tissues for a prolonged period of time. This project aims to investigate and develop an effective and safer treatment modality than intravitreal drug delivery: the trans-scleral sustained drug delivery. The project will explore the mechanisms of crystalline hydrophobic compounds crossing sclera, choroid, retinal pigment epithelium, and retina reaching vitreous to identify the key influential factors to the efficiency of the drugs crossing. The intraocular pharmacokinetics of these crystalline hydrophobic compounds will be characterized following subtenon injection and the kinetics will serve as a start point to further optimize by using biomaterials to achieve a slow release and sustained intraocular drug level. The interactive modalities and features as well as their interaction controls between biomaterials and the study compounds will be a major aspect of this project. We will try various constructive techniques including layer by layer and mosaic etching to build models of drug-biomaterial episcleral devices including episcleral sustained drug release membrane as well as episcleral injectable colloids. The intraocular pharmacokinetics of the study drug will be characterized and optimized by varying the construction techniques and components of the episcleral drug device and by comparison with the kinetics following native drug application. The optimized episcleral devices will be evaluated on animal eye disease models for their safety and efficacy.

眼球后段疾病如葡萄膜炎和增殖性视网膜病变等是慢性，难治性，和致盲率高的眼病，在我国广泛流行。有效治疗这些疾病的关键是在疾病组织内维持有效药物浓度相当长时间。该项目旨在研究比目前眼内直接给药更安全的一种治疗方法-经巩膜缓释眼内给药。项目重点研究疏水结晶类药物经巩膜给药的机理和可行性，研究此类药物透过眼球壁各层的机理和影响因素，巩膜表面使用后眼内药代动力学模型特点。研究此类药物与可降解生物材料结合的模式和与药物缓释之间的关系，发现对药物缓释有关键作用的调控因素。试用层层设计，马赛克组合结构构建巩膜表面药物缓释载体，并对其体外和体内药物释放动力学、生物安全性和有效性、药物量效关系等一系列基础科学问题进行研究。 开发出具有合理眼部药代动力学参数的巩膜表面缓释药膜和药物微球，在动物眼病模型上评价其局部给药治疗眼球后段疾病的安全性和有效性。

很多眼球后段疾病如葡萄膜炎、增殖性视网膜病变都是慢性、难治性、高致盲率眼病，在我国广泛流行。使药物在病灶部位长期维持在有效浓度之上是治疗这类疾病的关键。玻璃体腔注射是临床上主流的眼后段疾病给药方式，然而该方法具有损伤性，对眼壁组织造成破坏。同时由于药物清除速度较快，玻璃体腔注射往往需要频繁给药，因而还会增加感染、视网膜出血和脱落的风险。本项目研究了一种相比玻璃体腔注射更为安全的给药策略，即经巩膜给药。首先我们研究了疏水结晶类药物（以曲安奈德为模型药物）与眼壁的作用机理，眼内色素以及巩膜、脉络膜血流和淋巴循环对经巩膜给药的影响。在此基础上我们设计构建了一种负载曲安奈德的PCL缓释药膜用于经巩膜给药，该药膜可以改变药物的释放行为（由一级释放变为缓慢持续释放）并显著延长药物在脉络膜、视网膜的驻留时间（脉络膜驻留时间达到筋膜下注射的2倍）。此外，我们还研究了眼压对经巩膜给药的影响以及脉络膜上腔注射作为另一种有效的眼后段疾病给药方式的可行性。这些研究和成果立足于学科前沿，对我国构建有实际临床价值的经巩膜给药装置具有重要的指导作用。