INTRAVITREAL DRUG DELIVERY

该项目广泛的长期目标是：a)调查 控制玻璃体药物清除的物理化学性质 和b)开发可植入的缓释装置，以维持 玻璃体和玻璃体内药物的治疗性、无毒性浓度 视网膜。具体目标是(1)开发可植入释放装置 以下模型化合物在体内以稳定的速度持续2个月： 庆大霉素、更昔洛韦、氟比洛芬、地塞米松、奥曲肽和 环孢素A微丸将以两种不同的比例进行包衣 惰性聚合物，一种(聚乙烯醇)透水，另一种 (乙烯-醋酸乙烯酯)是不透水的。药物的溶解度 聚合物的比例将决定释放速率。(2)种植 兔眼的结膜下和玻璃体内植入装置。 测量稳定状态的玻璃体和含水药物水平将使 吸收率和排除率有待计算。(3)破坏色素沉着 并测量其对稳态药物水平的影响。 将通过静脉注射碘酸钠来杀死RPE，以及 对药物水平的影响将指示药物中的速率决定步骤 从玻璃体中吸收/消除。(4)评价缓释效果 环孢素A和地塞米松在动物治疗中的应用 葡萄膜炎和增殖性玻璃体视网膜病变(PVR)模型。模特们将 BE S抗原在大鼠和兔葡萄膜炎及成纤维细胞注射中的应用 PVR的兔子。与医疗保健相关：每200人中就有1人患上 葡萄膜炎导致30,000多例法律失明。PVR一直是 被认为是视网膜眼科医生面临的最严重问题。 植入性缓释环孢素(可见葡萄膜炎) 而地塞米松(PVR中的地塞米松)可能会在治疗方面取得重大进展。 更好地理解理化性质对药物的影响 可以预期吸收进入视网膜/玻璃体和从视网膜/玻璃体清除 帮助药物和给药系统的设计，特别是后部的 节段性疾病。

The broad long-term objectives of this project are to: a) investigate physicochemical properties governing drug elimination from the vitreous and b) develop implantable sustained release devices to maintain therapeutic, non-toxic concentrations of drugs in the vitreous and retina. Specific Aims are to (1) Develop implantable devices releasing the following model compounds at a steady rate for 2 months in vivo: gentamicin, ganciclovir, flurbiprofen, dexamethasone, octreotide and cyclosporine A. Pellets of drugs will be coated in varying ratios of two inert polymers, one (polyvinyl alcohol) is water permeable and the other (ethylene vinyl acetate)) is impermeable. The solubility of the drugs and the polymer ratio will determine the release rate. (2) Implant devices subconjunctivally and intravitreally into rabbit eyes. Measurement of steady state vitreous and aqueous drug levels will enable absorption and elimination rates to be calculated. (3) Disrupt pigmented epithelial function and measure the effect on steady state drug levels. Sodium iodate will be administered intravenously to kill the RPE, and effects on drug levels will indicate the rate determining steps in drug absorption/elimination from the vitreous. (4) Evaluate sustained release devices of cyclosporine A and dexamethasone in the treatment of animal models of uveitis and proliferative vitreoretinopathy (PVR). Models will be S antigen in rat and rabbit for uveitis and fibroblast injection in the rabbit for PVR. Relevance to health care: 1 in 200 people develop uveitis which causes over 30,000 cases of legal blindness. PVR has been identified as the most serious problem faced by retinal ophthalmologists. Implantable sustained release cyclosporine (in sight threatening uveitis) and dexamethasone (in PVR) may prove a significant advance in treatment. Better understanding of the effect of physicochemical properties on drug absorption into and elimination from the retina/vitreous can be expected to aid the design of drugs and delivery systems, especially for posterior segment diseases.