Topical noninvasive retinal drug delivery of a tyrosine kinase inhibitor: 3% cediranib maleate cyclodextrin nanoparticle eye drops in the rabbit eye

Abstract

Purpose: Tyrosine kinase inhibitors inhibit VEGF receptors. If delivered to the retina, they might inhibit oedema and neovascularization such as in age-related macular degeneration and diabetic retinopathy. The aim of this study was to formulate cediranib maleate, a potent VEGF inhibitor, as γ-cyclodextrin nanoparticle eye drops and measure the retinal delivery and overall ocular pharmacokinetics after a single-dose administration in rabbits. Methods: A novel formulation technology with 3% cediranib maleate as γ-cyclodextrin micro-suspension was prepared by autoclaving method. Suitable stabilizers were tested for heat-stable eye drops. The ophthalmic formulation was topically applied to one eye in rabbits. The pharmacokinetics in ocular tissues, tear film and blood samples were studied at 1, 3 and 6 hr after administration. Results: γ-cyclodextrin formed complex with cediranib maleate. The formation of γ-cyclodextrin nanoparticles occurred in concentrated complexing media. Combined stabilizers prevented the degradation of drug during the autoclaving process. Three hours after administration of the eye drops, treated eyes showed cediranib levels of 737 AE 460 nM (mean AE SD) in the retina and 10 AE 6 nM in the vitreous humour. Conclusions: Cediranib maleate in γ-cyclodextrin nanoparticles were stable to heat in presence of stabilizers. The drug as eye drops reached the retina in concentrations that are more than 100 times higher than the 0.4 nM IC 50 value reported for the VEGF type-II receptor and thus, presumably, above therapeutic level. These results suggest that γ-cyclodextrin-based cediranib maleate eye drops deliver effective drug concentrations to the retina in rabbits after a single-dose administration.

An Update on Strategies to Deliver Protein and Peptide Drugs to the Eye

“…Cediranib levels obtained in the retina were 100 times higher than the reported IC 50 value of the type-II VEGF receptor. This study demonstrated the ability of cyclodextrin to act as a permeability enhancer for ocular protein and peptide delivery …”

“…This study demonstrated the ability of cyclodextrin to act as a permeability enhancer for ocular protein and peptide delivery. 176 5.1.1.2. Chelating Agents.…”