A novel approach of increasing bioavailability of drug molecules to the posterior ocular segment through topical administration using penetration enhancing agents

Abstract

AbstractA major cause of blindness worldwide is disease and damage in the posterior ocular segment. Due to poor penetration of therapeutic molecules, topical eye drops tend to be the least effective. We demonstrate a potential approach of penetration enhancement in topical drug formulations for such diseases using three penetration enhancing agents (PEAs) — an in‐house synthesized novel helical polymer and two commonly used cell penetrating peptides (CPPs), TAT and Penetratin, to enable increased penetration of the most commonly used anti‐inflammatory drug, dexamethasone sodium phosphate (DSP). A rapid and cost‐effective ex‐vivo screening model of excised porcine cornea and sclera is used to assay trans‐corneal/scleral penetration of the three PEAs and results quantified using UV & fluorescence spectroscopy for PEAs and by high performance liquid chromatography (HPLC) for DSP. All three PEAs effectively cross both the cornea and sclera individually. A significant enhancement of DSP trans‐corneal/scleral permeation after topical application with PEAs is observed. ZO‐1 immunostaining of the tight junctions in corneal epithelium demonstrated intact tight junctions and transepithelial electrical resistance (TEER) measurements of the corneal epithelium before and 60 minutes after application show very negligible to no difference, thus proving no damage has been done to the integrity of corneal barrier and barrier function. Finally, in‐vitro cytotoxicity of PEAs was determined using MTT assays in ARPE‐19 and HCE‐2 cells, whilst immunostaining with β‐III tubulin was used in assays involving adult rat primary retinal neurons. None of the PEAs exhibit any trace of cytotoxicity. We conclude that CPPs are able to increases the efficiency of drug delivery through the cornea and improve the chances of drug delivery to the posterior ocular segment.