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Injectable Extended Release Local Anesthetic Drug Delivery System For The Treatment Of Post-operative Pain
Brett Davis, MS, Sierra Erickson, BS, Susan Wojtalewicz, BS, Andrew Simpson, MD, Himanshu Sant, PhD, Jill Shea, PhD, Bruce Gale, PhD, Jay Agarwal, MD.
University of Utah, Salt Lake City, UT, USA.

Purpose: The United States is experiencing an opioid crisis, with over 14,000 deaths from prescription opioids annually. Surgery is a critical point where patients are at risk of developing or worsening opioid-misuse disorders with approximately 10% of patients going on to long-term opioid use. Clinicians need safe and effective non-opioid alternative treatment strategies for the management of post-operative pain. The purpose of this study was to perform proof-of-concept testing of a novel sustained release local anesthetic drug delivery system that could be used to control post-operative pain. Methods: Bupivacaine-loaded lipid emulsions were created by admixing 1.5% w/v bupivacaine freebase with off-the-shelf parenteral fat emulsion 15% w/v Intralipid®, and then re-homogenizing by high-speed homogenization for 2 cycles of 5 minutes at 10,000 RPM. The resulting bupivacaine-loaded emulsion was entrapped into a crosslinked-hyaluronic acid hydrogel (HALA) by mixing with 1.33% w/v thiol modified hyaluronic acid and 0.833% w/v thiol reactive crosslinker poly(ethylene glycol) diacrylate. To determine the bupivacaine rate of release from the formulation, 0.5ml (n=6) of the gel was placed into a 10kDa molecular weight cut-off dialysis bags and then submerged in 40ml of phosphate buffered saline (PBS). The PBS was collected and replaced at predetermined time points to be used for UV-Vis spectroscopy. A rat sciatic nerve block model and Hargreaves thermal nociception assay was used to assess the anesthetic efficacy of the HALA formulation. The paw withdrawal latency (PWL) was measured at predetermined time points after injection to the right sciatic nerve of healthy male Sprague Dawley rats. Groups consisted of: 0.2ml 1.5% w/v bupivacaine HALA (n=6), 0.2ml 1.5% w/v bupivacaine-loaded emulsions (n=6), 0.2ml Exparel® (1.33% w/v bupivacaine) (n=6), and 0.2ml 0.25% w/v bupivacaine HCL (n=6). Results: In vitro drug rate of release testing found average bupivacaine cumulative release values of 74.0±2.12% at 20 hours, 90.9±2.-5% at 44 hours, and 97.3% at 68 hours. The Hargreaves assay found that HALA group had average PWL above pre-operative baseline values for 4 hours, followed by Exparel® for 3 hours, bupivacaine-loaded emulsions for 2 hours, and 0.25 % bupivacaine HCL for 1 hour. All the groups except Exparel® had PWL values signifying onset of anesthesia at the first time point (1 hour), suggesting a delayed release of bupivacaine from Exparel®. Peak average PWL amplitude of each group was: 15.0 seconds - HALA, 11.1 seconds - bupivacaine-loaded emulsions, 9.17 seconds Exparel®, and 10.0 seconds - 0.25% bupivacaine HCL. Area under the curve (AUC) analysis above baseline was performed to quantify the anesthetic effect over the study and found the following: 1174 AUC - HALA, 449 AUC - bupivacaine-loaded emulsions, 264 AUC Exparel®, and 187 AUC - 0.25% bupivacaine HCL. Conclusion: Results of this study indicate that the lipid emulsion-loaded hydrogel delivery system can provide greater and longer duration of anesthesia than current clinically available options. Additionally, the HALA formulation had no delay in onset, but the current clinically available Exparel® did. The HALA formulation has potential to be a new effective alternative to the current clinically available options for prolonged local anesthesia.


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