Formulation, Optimization and Evaluation of an Ion-Activated Ocular In-Situ Gel of Timolol Maleate Using Natural Gelling Agents (Sodium Alginate and Gellan Gum) for Sustained Glaucoma Therapy

Conventional ophthalmic eye drops suffer from poor ocular bioavailability, typically below five percent, owing to rapid precorneal drainage, tear turnover and nasolacrimal clearance, which shorten the residence time of the drug and necessitate frequent dosing. The present study was undertaken to formulate, optimize and evaluate an ion-activated ocular in-situ gel of the antiglaucoma β-blocker timolol maleate using the naturally derived, ion-sensitive gelling polymers sodium alginate and gellan gum, with the aim of prolonging precorneal residence time, sustaining drug release and reducing dosing frequency. Nine formulations (F1–F9) were prepared by the cold (dispersion) method with the drug fixed at 0.5% w/v and varying polymer and calcium chloride concentrations. Preformulation FTIR and DSC studies confirmed the absence of any drug–polymer interaction. All formulations were transparent, of ocular-compatible pH (6.6–7.3), exhibited pseudoplastic flow and underwent immediate sol-to-gel transition on contact with simulated tear fluid, with viscosity rising sharply after gelation. Drug content was uniform (96.2–101.4%). In-vitro release across F1–F9 was sustained over 8–12 hours; the optimized batch F7 released 92% of drug in 12 hours without any burst effect, best fitting the Korsmeyer–Peppas model (R² = 0.989, n = 0.67) indicative of non-Fickian (anomalous) transport. Ex-vivo corneal permeation of F7 was gradual and sustained, reaching 82.16% at 8 hours, markedly outperforming a marketed solution. The optimized formulation remained physically and chemically stable over three months under ICH long-term and accelerated conditions. The developed natural-polymer ion-activated in-situ gel is a promising, patient-friendly alternative to conventional timolol eye drops for glaucoma management.