A gellan gum-based in situ gel for prolonged ocular retention of ruxolitinib in dry eye disease.

The local delivery of JAK inhibitors for dry eye disease (DED) remains challenging due to poor drug solubility and rapid ocular clearance. This study reports an ion-sensitive in situ gelling system for ruxolitinib (Ru) using polyvinylpyrrolidone-K12 and gellan gum to enhance solubility and ocular retention. The optimized Ru gel exhibited shear-thinning behavior and rapid ion-activated gelation. In vitro permeation studies indicated that the gel matrix did not impede Ru diffusion. In scratch assays and Transwell assays performed under hypertonic stress conditions, the Ru gel demonstrated a more pronounced pro-migratory effect on cells within the scratch assay. This observation may indicate variations in the gel matrix's mechanism of action across different cellular migration patterns. Pharmacokinetic evaluation in rabbits demonstrated a 5.14-fold increase in aqueous humor exposure (AUC) compared with Ru solution, without significantly altering Tmax, MRT, or t1/2, suggesting that enhanced efficacy stems from prolonged precorneal retention rather than improved corneal penetration. In a benzalkonium chloride-induced rat DED model, the Ru gel significantly restored tear secretion, prolonged tear film break-up time, and repaired corneal integrity to levels comparable to healthy controls. While blank gel provided physical protection and reduced pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) possibly through lubrication and barrier effects, Ru-loaded gel uniquely promoted histological recovery of corneal epithelium and conjunctival goblet cells. These findings demonstrate that the engineered Ru gel is a safe and potent therapeutic platform that enhances ocular exposure and mitigates inflammation through prolonged retention and pharmacological repair, offering a promising strategy for DED management.