A combined reverse thermal gel-polymeric micelle system for sustained delivery of ophthalmic drugs

Delivery of drugs to the eye is a challenging endeavor due to the myriad anatomical and physiological barriers preventing intraocular absorption of molecules that either contact the anterior surfaces of the eye or are present in the bloodstream. Topical administration---the workhorse of ophthalmic drug delivery---suffers from numerous drawbacks including poor intraocular bioavailability, excessive systemic absorption, need for frequent re-administration and a reliance on patient adherence for therapeutic efficacy, among others. To overcome these limitations, researchers have explored various controlled release drug delivery systems with the ultimate goal of sustaining consistent, localized drug levels at the target tissue thereby maximizing therapeutic efficacy and minimizing unintended adverse effects. Among the options explored, in situ-gelling polymeric systems may hold the most promise due to their ability to be administered directly at the target site by a minimally-invasive injection and form a stable physical gel while conforming to the specific anatomy of that space. To date, clinical application of such systems has been hindered by their limited ability to sustain long-term delivery of drugs. To overcome this limitation, we sought to develop a system comprising a reverse thermal gel (RTG) encapsulating drug-loaded polymeric micelles as a combined system for the sustained local delivery of poorly soluble drugs. The polymers comprising the RTG and the micelles---both novel---were first independently characterized as free-standing systems. The combined system was then evaluated and was found to retain the injectability and in situ gelling characteristics of the thermal gel, but additionally benefited from the superior ability of the entrapped micelles to encapsulate and sustain release of the poorly soluble corticosteroid triamcinolone acetonide (TA). Release of TA from the combined system was completely free of a burst release and was projected to continue at a steady rate for approximately twelve months. To our knowledge, this system is the first in the literature to achieve delivery time frames from an in situ-gelling polymer beyond a few months and has the potential to significantly improve delivery of TA and, more broadly, clinical treatment of posterior ophthalmic diseases.