BIOERODIBLE INTRAVITREAL DRUG DELIVERY SYSTEMS

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The broad long-term objectives of this project are to 1) develop an implantable, erodible drug delivery system for use in the treatment of proliferative vitreoretinopathy (PVR). 2) further evaluate the codrug concept as a means to achieve sustained therapeutic drug levels in the eye. A codrug is a conjugate formed by two or more drugs covalently linked together. When linked, codrugs have exceptionally low solubility so that pellets of codrug dissolve extremely slowly. Once in solution however the codrug is rapidly hydrolyzed to regenerate the two or more active drugs. Such a system enables sustained local drug levels to be achieved without resorting to polymers to control drug release. SPECIFIC AIMS are to a) Investigate the hydrolysis of a series of codrugs of the steroids triamcinolone, dexamethasone and triamcinolone acetonide with 5- fluorouracil in various pHs, serum and vitreous and determine the optimal chemical linkage. b) Prepare bioerodible, implantable, sustained release devices from these codrugs and determine their release in vitro. c) Measure release and tissue distribution in the rabbit model after intravitreal implantation. d) Determine the biocompatibility of these devices, e) Evaluate the efficacy of these agents against PVR in the rabbit model. RELEVANCE TO HEALTH CARE: The codrug concept offers a means to deliver a wide variety of drugs to the eye via bioerodible devices. In the present proposal codrugs will be examined as a means to treat PVR, identified in a recent survey as a major problem facing vitreoretinal surgeons.