In Situ Gel Formulation for Enhanced Ocular Delivery of Nepafenac

Abstract

Nepafenac is a water-insoluble nonsteroidal antiinflammatory drug that is available as an ophthalmic suspension (Nevanac®). Suspensions are undesirable for 2 reasons: they tend to cause foreign body sensation and lacrimation, which could limit residence time and drug bioavailability. This decreases the amount of time the drug has to reach the site of action, the cornea. Previously, we improved the solubility and ocular permeability of nepafenac by complexing the drug with hydroxypropyl-β-cyclodextrin. In this study, we used the complex to formulate an ion-activated in situ gel system using sodium alginate, Protanal PH 1033, to increase the residence time and to reduce repeat eye drop instillation. Rheological properties of the formulations revealed that the viscosity of the optimized formulation was increased 30-fold when exposed to the simulated tear fluid (35°C). Permeation studies showed that the drug concentration of the in situ formulations were approximately 10 times higher than the commercial product, Nevanac® (p < 0.001). In addition, the in situ gel formulations had 5-fold higher concentrations of nepafenac retained in the cornea when compared to Nevanac® (p <0.001). Finally, ex vivo drug distribution studies in the porcine eye perfusion model revealed a higher drug retention in various ocular tissues such as cornea, sclera, retina, as compared to Nevanac®.