Abstract
Efflux transporters such as P-glycoprotein (P-gp) and Multidrug resistance proteins-2 (MRP-2) are often highly expressed on cornea and conjunctiva, significantly restricting the absorption of topically administered drugs into the eye. We hypothesized that nanocarrier with P-gp and MRP-2 inhibitory activity may enhance drug permeation across the cornea. Due to ease in development and scale-up, a lipidic nanocarrier was proposed and therefore lipids and surfactants were screened for P-gp and MRP-2 modulation using erythromycin (Ery), a known substrate for both P-gp and MRP-2 as model drug and freshly excised goat cornea as membrane. Out of the studied lipids/surfactants, Peceol and Pluronic F127 showed maximum inhibitory effects against P-gp and MRP-2 and were used to develop efflux transporter inhibitory micelles (EXTRIN-micelles). Dynamic laser scattering showed that EXTRIN-micelles were 348 ± 14.5 nm with PDI <0.09. Preclinical studies in rabbits demonstrated significantly higher (p < 0.05) corneal retention of EXTRIN-micelles compared to solution. Further, EXTRIN-micelles delivered significantly higher (p < 0.001) Ery concentrations to aqueous humor compared to solution. In conclusion, EXTRIN-micelles are potential carriers for enhanced ocular delivery of drugs.
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