Fenofibrate microemulsion eyedrops for treating nitrogen mustard induced corneal injury

Vesicants are highly toxic chemicals used as warfare agents, primarily absorbed through the skin, inhalation, or ocular surface. Nitrogen mustard (NM), a potent vesicant, often leads to blindness due to the inadequacies of existing therapies. This study explores the role of peroxisome proliferator-activated receptor-α (PPARα) in NM-induced ocular injury and evaluates the efficacy of fenofibrate (Feno), a PPARα agonist, in preventing corneal injury progression. Feno, an FDA-approved oral medication used to treat dyslipidemia, has shown off-labelled potential in promoting corneal wound healing. However, its limited ocular distribution following oral administration reduces its therapeutic efficacy. We developed Feno-loaded oil-in-water microemulsion (Feno ME) eyedrop formulations to enhance aqueous solubility and ocular bioavailability of Feno, aiming to improve the therapeutic efficacy in treating NM-induced corneal injury. Feno ME exhibited a mean droplet size of approximately 20 nm, remained physically stable for at least twelve months, showed prolonged ocular retention, and demonstrated well-accepted rheological properties without inducing ocular irritation or toxicity. Furthermore, Feno ME demonstrated sustained drug levels in ocular tissues with minimal systemic absorption. A 14-day treatment with 0.5% Feno ME (3×/day) significantly reduced corneal-ulceration, neovascularization (NV), and opacity in NM-induced ocular injury in rats. Histopathological analysis confirmed preserved corneal integrity and reduced inflammation. Immunohistochemistry revealed that NM injury significantly reduced PPARα levels in the corneal epithelium, which was restored with Feno ME eyedrop treatment, suggesting PPARα as a promising drug target for NM-induced corneal injury. Our Feno ME eyedrop formulation represents an effective topical delivery platform that effectively mitigates NM-induced corneal injury and offers a novel therapeutic strategy for vesicant exposure.