Thermoresponsive Hydrogel Composite Devices for Cooling-Triggered Release of Therapeutics for Pain Relief

Easy, on-demand treatment of pain is achieved primarily by opioids, which are frequently administered orally (for on-demand relief) and have systemic effects. Unfortunately, these drugs are highly addictive; over 5 people per hour die from opioid abuse in the US alone. A safer, non-systemic mechanism for pain relief is therefore needed. Local anesthetics and nonsteroidal anti-inflammatory drugs (NSAIDs) have been explored for this purpose; they are non-addictive, provide excellent pain relief, and can (local anesthetics must) be delivered locally to minimize dosage and systemic side effects. However, an on-demand, minimally invasive method for local delivery is needed to enable these drugs to serve as a convenient replacement for opioids; external stimulus-triggered release from an implanted depot is one approach. Stimuli like light and ultrasound have been used to trigger drug release from implanted depots, however, these rely on energy input to tissue (provided by complex apparatus) and are thus not comparable to the ease of oral administration. We propose localized cooling as a stimulus. As icepacks are already applied to ease local pain, introducing a drug delivery mechanism switched “ON” by cooling would enable long duration, enhanced pain relief triggered by a method with which patients are already familiar. Herein, we demonstrate that cooling-triggered release of both local anesthetics and NSAIDs can be achieved using the well-known gel-to-sol transition that physically crosslinked thermoresponsive polymer hydrogels undergo upon being cooled below their LCST. We show that said hydrogels, loaded with a given anesthetic or NSAID, can be combined with a non-thermoresponsive membrane material to create implantable devices that demonstrate up to a ~40x increase in drug release rate upon cooling below body temperature.<br/><br/>We designed two separate thermoresponsive hydrogel composite devices. In the first, an aqueous solution of 35 w/v% Soluplus (a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer made by BASF) loaded with the NSAID Celecoxib (CXB) (8 w/w_Soluplus%) or Nile red (0.4 w/w_Soluplus%) was combined at various ratios with 3.1 w/v% sodium alginate (with 0.1% linear polyethyleneimine (LPEI) to enhance crosslinking). We then poured this mixture into a mold, and placed said mold into 3 w/v% calcium chloride for 30 minutes. The resulting gel device was composed of a crosslinked alginate matrix with scattered ~20-micron diameter domains of CXB-laden Soluplus. We explored the microstructure of these devices using scanning electron and confocal microscopy. We also explored cooling-triggered release of CXB or Nile red from them in-vitro and in cadavers. The second hydrogel composite device was made by creating solutions of 6 w/v% poly-n-isopropylacrylamide (PNIPAM) and either 2 w/v% Bupivacaine hydrochloride (BUP) or 0.2 w/v% fluorescein sodium (FL), allowing these solutions to physically gel at 31.5 °C for 48 hours, and encapsulating the resulting physical hydrogels inside chemically welded regenerated cellulose membranes. We then explored in-vitro cooling-triggered release of BUP and FL from these devices.<br/><br/>The alginate/Soluplus composites released Nile red and CXB ~100x faster ON (at 23 °C) vs. OFF (at 37 °C) in-vitro; a ~40x difference was seen when 29 °C and 35 °C were used as the ON and OFF temperatures, respectively. The latter temperatures represent icepack-cooled and uncooled temperatures 1 cm below the skin, as described in literature. Results in cadavers were similarly conclusive. The PNIPAM/cellulose composites released FL &gt;100x and BUP ~30x faster ON (at 25 °C) vs. OFF (at 31.5 °C). These temperatures represent icepack-cooled and uncooled temperatures in the subcutaneous layer. Hence, we have demonstrated in-vitro cooling triggered release of both an NSAID and a local anesthetic at temperatures achievable in-vivo. We are currently working to demonstrate this behavior in live Sprague-Dawley rats.