Mucoadhesive micellar eyedrops for the treatment of ocular inflammation.

Abstract

Efficient ocular drug delivery remains a significant challenge in treating eye inflammation due to physiological barriers such as the tear film and frequent blinking, which lead to rapid drug clearance. Commercial eyedrops, like Oceanside® (0.5 % loteprednol etabonate (LE) ophthalmic suspension), suffer from low ocular bioavailability and require frequent dosing to maintain therapeutic levels. To address these limitations, we developed a mucoadhesive micellar drug delivery system to enhance the bioavailability and retention of LE on the cornea. Our system employed polymeric micelles (MCs) functionalized with phenylboronic acid (PBA), which exhibited high conjugation efficiency to enable strong binding to the mucin-rich corneal layer. These MCs were synthesized using PBA-functionalized poly (ethylene glycol)-b-poly (N-(2-hydroxypropyl) methacrylamide-oligolactate) (PBA-PEG-b-p(HPMA-Lac_m)) and subsequently dispersed into a shear-thinning matrix solution to form a micellar eyedrop formulation. The resulting eyedrop demonstrated a sustained LE release over 12 days, enabling prolonged therapeutic exposure. In vitro, ex vivo, and in vivo studies confirmed enhanced mucoadhesion and extended corneal retention. The formulation was biocompatible with human corneal epithelial cells and demonstrated ocular safety in mice. In a murine model of electrocautery-induced corneal inflammation, a once-daily administration of LE-loaded PBA-MC eyedrops significantly reduced corneal opacity, preserved corneal structure, and lowered immune cell infiltration and cytokine levels. Notably, the therapeutic efficacy of the LE-loaded PBA-MC eyedrops matched that of commercial Oceanside®, which required four daily doses. These findings suggest that the engineered PBA-MC eyedrops could serve as a promising platform for ocular drug delivery, addressing the challenges associated with treating eye inflammation effectively. STATEMENT OF SIGNIFICANCE: Mucoadhesive nanoparticles used for ocular drug delivery often suffer from low attachment efficiency, limiting their effectiveness. Additionally, the lack of in vivo comparisons with commercial eye drops hinders evaluating their clinical benefits. To address these issues, we developed PBA-functionalized polymeric MCs to enhance the bioavailability of LE by increasing its retention on the corneal mucin layer. These MCs showed high PBA conjugation efficiency, a 12-day sustained release of LE, strong mucin adhesion, in vitro and in vivo biocompatibility. In a mouse model of corneal inflammation, a once-daily LE-loaded micellar eyedrop matched the efficacy of the commercial LE eyedrop (Oceanside®, 0.5 %), which was dosed four times daily, reducing corneal opacity, preserving corneal structure, and decreasing inflammation.