QbD-Driven Rational Design of Vancomycin-Loaded Nanocubosome In situ Ocular Gels: Augmenting Precorneal Retention and Improving Anti-MRSA Keratitis Treatment

INTRODUCTION: Vancomycin hydrochloride (VAN) is the treatment of choice for methicillin- resistant Staphylococcus aureus (MRSA) keratitis, but poor corneal penetration, epithelial toxicity, and the need for frequent dosing highlight the need for advanced formulations. This study aimed to develop a VAN-loaded nanocubosomal in situ ophthalmic gel to enhance corneal bioavailability and residence time. METHODS: VAN-loaded nanocubosomes (VAN-NCs) were prepared using a melt-dispersion emulsification technique based on Quality by Design (QbD) principles. The optimized nanocubosomes were incorporated into a pH-responsive in situ gel containing Carbopol 934 and HPMC E3. RESULTS: The optimized formulation VAN-NCs exhibited a mean particle size of 100.8 nm, low PDI (0.15), high encapsulation efficiency (91.9%), and zeta potential of -20.4 mV. Glyceryl monooleate concentration, Poloxamer 407 level, and sonication time were identified as critical factors, achieving a desirability of 0.975. The in situ gel showed rapid pH-triggered gelation, sustained vancomycin release (~90% over 24 h; n = 0.82), and significantly higher ex vivo corneal permeation compared with free VAN gel. Stability studies confirmed >95% drug content over 30 days. DISCUSSION: The optimized nanocubosomal in situ gel improved vancomycin ocular delivery by enhancing corneal permeation and sustaining drug release. The QbD-established design space confirmed formulation robustness and suitability of GMO-Poloxamer nanocubosomes for controlled ophthalmic antibiotic delivery. CONCLUSION: The VAN-NCs in situ gel demonstrated controlled drug release, enhanced corneal permeation, and good physicochemical stability. These results support its potential as an improved ocular delivery system for bacterial keratitis, warranting further in vivo evaluation.