Overcoming corneal barriers: Posaconazole loaded cationic surfactant vesicles for enhanced ocular permeability and anti-fungal efficacy

Abstract

Posaconazole (PCZ) is a broad-spectrum anti-fungal drug approved by FDA and currently used off-label for the treatment of fungal keratitis (FK). Although ocular route serves as the most bioavailable route for treating FK, delivery of PCZ to the eye remains a challenge due to poor permeation though the cornea and rapid elimination from the eye. Here we outline a comprehensive formulation development process, beginning with in silico studies, progressing through in vitro evaluations, and ultimately achieving therapeutic benefits in vivo. We report modified niosome-like surfactant vesicles, hereafter termed as NioTherms, formulated using a novel and simple heat-mix method, encapsulating PCZ for ocular administration in the form of an in situ gel. Excipient screening performed using in silico simulations highly correlate with in vitro studies (R²=0.77), guiding optimization by Quality by Design (QbD) approach for encapsulating PCZ in NioTherms resulting in particles with an average size of 180.7 ± 2.3 nm, zeta potential of +27.5 ± 2.2 mV and entrapment efficiency of 87.6 % ± 1.7 %. A 2-fold increase in both mucin binding and cellular uptake indicates a functional role of positive surface charge in enhancing mucoadhesive properties of PCZ-NioTherms. In an in vivo murine ocular keratitis model, we demonstrate a 2-fold enhancement in trans-corneal permeability of PCZ-NioTherms and a 3-fold reduction in fungal burden compared to the control standard of care, the PCZ solution. Owing to a facile formulation process, we anticipate that PCZ-NioTherms would serve as a clinically translatable and patient compliant therapeutic intervention for treating FK.