Cooling-Triggered Release Of Anesthetics From Thermoresponsive Gels For On Demand Pain Relief

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SUMMARY The growing severity of opioid addiction and abuse throughout the United States has led to increased interest in more targeted and controlled approaches to pain management. In particular, prolonged duration local anesthesia has the potential to treat both chronic and acute pain without the many disadvantages and risks of systemic therapies. It would be highly desirable for patients themselves to controllably and non-invasively trigger the release of an anesthetic to manage their own pain. To enable such capability, several approaches have been developed; the stimuli used in these systems, however, must be provided by complex apparatus that can send the necessary energy in photothermal, ultrasound, or electromagnetic form to trigger release. As a simpler alternative, we will develop a platform enabling cooling-triggered release of anesthetics from an implanted thermoresponsive polymer gel, such that application of ice or a cold pack to the skin triggers prolonged pain relief. This approach leverages a stimulus that patients already associate with temporary pain relief, i.e. cooling, and avoids the need for complex apparatus to deliver energy in the appropriate form for triggering. While degradation of injectable thermogelling formulations has been used to controllably release therapeutic molecules, to date there has been no exploration into the concept of utilizing the cooling- induced disassembly of the physically crosslinked gel that forms upon injection of these formulations (due to warming from room temperature to physiological temperature). We will exploit cooling-induced liquification of a physically crosslinked gel to trigger release of a payload sequestered within the gel. Release rate will be modulated by a rate-controlling membrane surrounding the reservoir. We will first develop appropriate formulations to characterize how this concept enables cooling-triggered release of a model drug in vitro, and then move to in vivo studies that will demonstrate the stability of this platform at physiological temperature and the release of a model payload, Nile Red, upon application of ice to the skin. Additionally, we will characterize the release behavior of payloads modeling analgesic peptides. Finally, we will demonstrate the ability of a thermoresponsive polymer to stably load a typical anesthetic, bupivacaine, when physically crosslinked at physiological temperature, and, upon cooling, slowly release this therapeutic for prolonged duration local anesthesia. The end result of this research effort will be the development of an implantable thermoresponsive therapeutic formulation that provides prolonged pain relief via local anesthetic delivery upon cooling, establishing cooling as a new stimulus for therapeutic release strategies.