Ion-activated gellan gum in situ gel for prolonged ocular administration of tofacitinib citrate: An innovative treatment approach for dry eye disease.

Abstract

This study developed a novel tofacitinib citrate-loaded in situ gel (TFC-ISG) using low-acyl gellan gum to enhance ocular retention and bioavailability for improved dry eye disease (DED) treatment. This formulation remained stable after storage at 40 °C/25 % RH for 6 months. It demonstrated rapid gel formation when mixed with artificial tears and exhibited shear-thinning properties. The ion-triggered sol-gel transition of gellan gum did not impede drug diffusion, as evidenced by unaltered release profiles and corneal/scleral permeability. Compared to the TFC solution formulation, this preparation showed significantly prolonged ocular residence time and possessed excellent biocompatibility (human corneal epithelial cell viability > 80 % at 40 μg/mL concentration, and was non-irritating to rabbit eyes). Pharmacokinetic analysis in rabbits showed that TFC-ISG significantly increased ocular bioavailability (AUC) and Cby twofold compared to the TFC solution. In the benzalkonium chloride-induced DED rat model, TFC-ISG demonstrated superior efficacy over commercially available cyclosporine ophthalmic emulsion (0.05 %) and sodium hyaluronate eye drops (0.3 %). It effectively restored tear secretion, tear film stability, and ocular surface integrity, concomitant with significant down regulation of key inflammatory mediators (TNF-α, IL-1β, IL-18, MMP-2, MMP-9, IL-6), thereby blocking ocular surface inflammatory pathways. This synergistic dual action - concurrently restoring ocular surface function and suppressing inflammation - effectively mitigated DED progression. Thus, TFC-ISG emerges as a highly promising novel formulation for DED treatment, thereby offering a valuable new therapeutic option.