INTRAVITREAL DRUG DELIVERY

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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.