(F-222) Cooling-Triggered Release of Therapeutics from Physically Crosslinked Hydrogels

Introduction:: Non-invasive, on-demand treatment of pain (both chronic and acute) is currently achieved primarily through the use of orally administered opioids. Unfortunately, opioid addiction and abuse result in 5 deaths per hour in the US alone. Local anesthetics (like bupivacaine) offer a potent, non-systemic, non-addictive alternative. However, an on-demand, external stimulus-triggered delivery mechanism is needed to make them a viable, convenient replacement for opioids. Stimuli like electromagnetic radiation and ultrasound have been used to trigger release of various other drugs from subcutaneous drug depots (1); however, these require both energy input and complex apparatus and are thus not comparable to the ease of oral administration. We propose localized cooling as a safe, convenient stimulus. As icepacks are already widely used to temporarily ease local pain, a drug delivery depot switched “ON” by cooling a region of interest could enable long duration, enhanced pain relief triggered by a method with which patients are already familiar. Herein, we describe an approach for cooling-triggered drug release from drug-loaded physically crosslinked thermoresponsive polymer hydrogel domains within a different non-thermoresponsive hydrogel. The thermoresponsive hydrogel releases the drug when cooled below its lower critical solution temperature (LCST) (ON state), but not at body temperature above its LCST (OFF state), while the non-thermoresponsive hydrogel acts as a rate-limiter and maintains robustness of the depot.


Materials and Methods:: We loaded 1%w/w_gel Nile red (NR, as a model molecule for bupivacaine, our therapeutic of interest) into Soluplus (a thermoresponsive polyvinyl caprolactam copolymer from BASF) solution (35% w/v). We then dispersed this solution in 3.5% w/v alginate solution at a 1:1 ratio. Next, we poured this dispersion into a 400 µl mold of appropriate shape (disks, flat sheets, etc.), then dipped said mold in 37°C 3% CaCl₂ for 30 minutes to crosslink the alginate. To characterize the microstructure of the resulting materials, we used SEM (not shown) and confocal microscopy. We also characterized cooling-triggered release from these devices by placing them in 10 ml wells of simulated body fluid (SBF) (after 24 hrs. burst release into 37°C SBF) and varying their temperature between 37°C and 23°C.




Results, Conclusions, and Discussions:: Results: When observed at 40x via confocal microscopy, the crosslinked alginate-Soluplus dispersion revealed a domain structure (also seen using SEM) in which NR was mostly confined to Soluplus domains (Figs. 1A and 1B). These devices, when placed in wells containing SBF, displayed a dramatic response to cooling to 23°C (below the LCST of Soluplus); in the 24 hours prior to cooling (held at 37°C), only ~1% of the NR payload was released, however, upon cooling to 23°C, nearly 20% of the payload was released within 3 hours (Fig. 1C).



Conclusions: The devices described above are able to sequester NR at body temperature and release it rapidly upon cooling. Our results demonstrate that physically-crosslinked thermoresponsive polymer hydrogels have great potential to enable convenient, on-demand cooling-triggered release of therapeutics. Ongoing work is focused on further optimizing the system for bupivacaine release.






Acknowledgements (Optional): :

References (Optional): : 1. 1. Timko, Brian P., Tal Dvir, and Daniel S. Kohane. "Remotely triggerable drug delivery systems." Advanced materials 22.44 (2010): 4925-4943.