Loteprednol etabonate nanostructured lipid carriers for enhanced ocular bioavailability

Abstract

Loteprednol etabonate (LTP), a corticosteroid approved for management of post-operative ocular inflammation and dry eye symptoms, suffers from limited ocular bioavailability and high dosing frequency in its current marketed form, Lotemax® suspension. The current study reports the development and optimization of a novel nanostructured lipid carrier (NLC) system for LTP, designed to overcome these limitations through enhanced corneal penetration, sustained release, and improved therapeutic efficacy. Excipient screening assessment identified Gelucire 44/14, Miglyol 829, and Tween 80 as optimal solid lipid, liquid lipid, and surfactant, respectively, for LTP-NLC formulation. LTP-NLCs incorporating Transcutol® P as a permeation enhancer, and LTP-NLCs loaded into gellan gum-based ion-sensitive in situ gels, were systematically investigated. A Box-Behnken design enabled optimization of formulation variables, achieving ∼200 nm particle size with > 98% entrapment at 0.5% w/w drug load through precise control of lipid/surfactant balance and homogenization parameters. The optimized LTP-NLCs demonstrated excellent physicochemical stability (>3 months), amorphous drug dispersion within NLCs, and suitable rheological behavior. In vitro drug release studies (USP App IV) and ex vivo permeation studies across corneal and conjunctival tissues showed sustained release for LTP-NLCs compared to Lotemax®, with superior transcorneal permeation and minimal conjunctival loss. Incorporation of LTP-NLCs into gellan gum loaded in situ gels increased ocular retention but reduced permeability due to high viscosity. On the other hand, Transcutol® P markedly improved the transcorneal flux of LTP-NLCs and enhanced cellular uptake in human corneal epithelial cells. All formulations were non-irritant (HET-CAM), biocompatible, and maintained > 80% cell viability. Overall, the present work introduces a very promising LTP-NLC platform with demonstrated superiority over existing therapies, offering a strategy for enhancing ocular drug delivery, reducing dosing burden, and improving patient outcomes.

Keywords: Corneal permeability; In vitrodrug release; Lipid nanoparticles; Loteprednol; Nanoparticle-loadedin situforming gels; Nanostructured lipid carriers; Ocular bioavailability; Ophthalmic drug delivery.