Thermoresponsive Hydrogels with Tunable Viscoelasticity for Extended Ocular Drug Delivery

The conformation of charged polymers is heavily dependent on interactions with the surrounding salt ions. By adding calcium ions to hyaluronan-Pluronic F-127 complexes, we prepared colloidal coacervates with decreased viscosity at cold temperatures (<i>G</i>' of 10 Pa) and enhanced mechanical properties at physiological temperatures (<i>G</i>' of 19 kPa) that improved the stability of the gel and prolonged drug release. The release of ophthalmic drugs, brinzolamide, dorzolamide, and dexamethasone, was tuned from 2 weeks to four months by changing drug lipophilicity. The low-viscosity hydrogel enabled topical ocular administration as eye drops and injections via thin needles (29G) under the conjunctiva. The precorneal residence time of glaucoma drug brinzolamide was extended over 48 h after topical administration and over 23 days after subconjunctival injections in rabbits. These findings suggest an approach to improve the viscoelasticity of eye drops and injectables, as well as to prolong drug delivery times via hydrogel systems.