Ion-Activated Mucoadhesive in Situ Gel Incorporating Terbinafine-Loaded NLCs Promotes Ocular Penetration and Retention for Enhanced Fungal Keratitis Therapy

Fungal keratitis (FK) is a sight-threatening infection with poor outcomes due to rapid tear clearance and insufficient corneal penetration. To overcome the limitations, we developed an ion-activated mucoadhesive in-situ gelling system (TH-NLC-ISG) integrating terbinafine-loaded nanostructured lipid carrier (TH-NLC) into a gellan gum/carboxymethyl chitosan matrix. The optimized formulation exhibited a particle size of 25.27 ± 0.75 nm. Upon contact with simulated tear fluid, the formulation underwent rapid sol-gel transition, achieving a 70-fold viscosity increase (34°C, shear rate 1 s -1 ), critical for prolonged ocular residence. Fluorescence imaging demonstrated ocular retention of fluorescein sodium-labeled TH-NLC-ISG exceeding 60 min, significantly longer than the non-gelling control. In vivo pharmacokinetic studies revealed markedly improved ocular bioavailability, with higher area under the concentration in ocular tissues-time curve of TH in the TH-NLC-ISG group compared to TH-NLC. Corneal penetration studies confirmed that TH-NLC-ISG exhibited longer corneal retention time and higher corneal drug retention compared to TH-NLC. The formulation demonstrated excellent ocular biocompatibility in vitro and in vivo . TH-NLC-ISG exhibited potent in vitro antifungal activity against Fusarium solani. and Aspergillus flavus. , with a lower MIC 50 value than TH suspension. In rabbits and mice FK models, TH-NLC-ISG group achieved complete corneal healing, reduced clinical scores and corneal perforation rates, displaying efficacy superior to conventional natamycin eye drops. By synergistically augmenting retention and corneal permeation, TH-NLC-ISG provides a transformative strategy for enhanced fungal keratitis therapy. • An innovative ion-activated in situ gelling system integrating nanostructured lipid carriers (NLCs) into a gellan gum/carboxymethyl chitosan (GG/CMCS) matrix was engineered. • The formulation utilizes an ion-triggered sol-gel transition (70-fold viscosity increase) and electrostatic mucoadhesion to overcome rapid tear clearance. • Synergy between NLCs (penetration) and smart hydrogel (retention) significantly enhanced ocular bioavailability and corneal drug retention. • The therapeutic platform demonstrated superior efficacy over commercial natamycin in resolving fungal keratitis in animal models.