Microsphere-loaded dual-response in situ gel for enhanced ocular drug delivery.

Glaucoma is one of the most common blinding eye diseases worldwide. The limited ocular surface retention leading to a short duration of efficacy is the challenge in topical ocular drug delivery for glaucoma treatment. In this study, we developed a microsphere-in-situ gel composite drug delivery system (MPs-DSISG) containing Eudragit RS PO microspheres and a cation- and temperature-sensitive in situ gel, exhibiting dual-response properties. Precorneal fluorescence retention and tear elimination kinetics experiments confirmed that the ocular residence time of MPs-DSISG was longer than that of commercially available formulations and drug solutions. Besides prolonged retention time, the incorporated microspheres exhibited affinity for corneal epithelial cells and embedded themselves in the superficial layers of the conjunctiva, Tenon's capsule, episclera, and sclera. This enabled MPs-DSISG to achieve a 24 h intraocular pressure reduction, thus substantially reducing the dosing frequency. MPs-DSISG also demonstrated good biocompatibility‌ without ocular irritation and disturbing the tear film. In conclusion, this study demonstrates that incorporating microspheres into an in situ gel prolonged ocular retention and enhanced sustained drug efficacy, offering a promising improved treatment for anterior segment diseases.