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Purpose: Intra-ocular injection of biologics targeting VEGF is currently the standard of care for retinal vascular diseases. Delivery of potent small molecules to the retina as eye drops would be a treatment paradigm shift but remains an unmet need due to insufficient retinal delivery. We aimed to design compounds with the physicochemical properties required for eye drop delivery in large eyes using ex vivo permeability modelling.

Methods: Full thickness fresh porcine eye tissue was clamped into a scaffold with drug formulations nearest the sclera. Tissues were dissected at 24 h and compound levels analysed by mass spectrometry. 186 inhibitors were screened and a further 80 compounds were rationally designed based on chemical properties. For PK in a large eye, pigmented rabbits were administered a single eye drop for successive timepoints or dosed bid for 6 days. Eyes were dissected into regional segments …