Sustained-release gel for multi-day control of postoperative pain

主要调查者：奥弗斯特里特，德里克·J 摘要 索诺兰生物科学公司。 SBIR PA-21-259：第一阶段 在美国，每年约有1400万例手术与中度到中度- 术后剧烈疼痛，休息时至少持续三天。据报道，疼痛是 住院手术后延迟出院的最常见原因是 门诊手术后非计划入院。术后疼痛的治疗 对临床医生来说，这是一个具有挑战性的场景，因为它是资源密集型的，而且经常 涉及与不良反应相关的阿片类药物。此外，糟糕的是 有管理的疼痛会导致患者痛苦并增加并发症的风险。 目前的最佳做法支持使用多模式止痛方案，这些方案依赖于 多种药物，以抵消对阿片类药物的需求。局麻药是一种关键成分 因为它们可以有效地减轻局部疼痛，同时 具有良好的安全状况。不幸的是，局部麻醉剂分子仅在 长达8小时和可用的缓释产品在12-24小时后的疗效有限 手术后。市场领先者是Exparel(布比卡因脂质体)，它正在达到 2021年销售额将达到5亿美元。仍然有巨大的需求和商业机会 局部麻醉剂，提供至少三天的止痛，这将延续到 家庭环境，有可能使患者在没有阿片类药物处方的情况下安全出院。 我们开发了一种专有的缓释载体SB Gel，它可以混合 在使用时使用局部麻醉剂布比卡因，并作为水溶液使用， 在手术部位形成一种柔软的凝胶。SB凝胶提供布比卡因扩散释放 数天后在体内溶解约三周。在猪皮肤和肌肉切开模型中， 布比卡因SB凝胶具有持续120小时的镇痛作用。明显更强大的力量 在接受SB Gel+布比卡因的部位与接受SB Gel+布比卡因的部位相比，伤口处的疼痛是可以容忍的 分别于术后24、48、72、96、120小时观察。 我们现在建议完成一项第一阶段项目，以确定布比卡因的可行性- 加载SB Gel作为同类中最好的缓释局部麻醉剂。在目标1中，我们将研究 SB凝胶+布比卡因的剂量反应，比较SB凝胶+布比卡因的疗效 所有FDA批准的缓释局麻药，并评估对 伤口愈合。在目标2中，我们将评估安全性，包括全身毒性、全身暴露 布比卡因，以及对肌肉和周围神经的毒性。项目圆满完成 将为扩大制造和未来支持IND的毒理学研究做好准备。

Principal Investigator: Overstreet, Derek J. Abstract Sonoran Biosciences, Inc. SBIR PA-21-259: Phase I About 14 million surgeries annually in the United States are associated with moderate-to- severe postoperative pain lasting at least three days at rest. Pain has been reported to be one of the most common reasons for delayed discharge following inpatient procedures and for unplanned hospital admissions following outpatient procedures. Treatment of postoperative pain presents a challenging scenario for clinicians because it is resource-intensive and frequently involves opioid medications which are associated with adverse effects. Moreover, poorly managed pain leads to patient suffering and increased risks of complications. Current best practices support the use of multimodal analgesia regimens which rely on multiple classes of drugs to offset the need for opioids. Local anesthetics are a critical component of multimodal analgesia because they can provide a potent reduction of pain in a local area while having a favorable safety profile. Unfortunately, local anesthetic molecules only remain active for up to eight hours and available extended-release products have limited efficacy beyond 12-24 hr postoperatively. The market leader is Exparel (liposomal bupivacaine), which is on pace to reach $500 million in sales in 2021. There remains a significant need and commercial opportunity for a local anesthetic that provides analgesia for at least three days, which would carry over into the home setting, potentially enabling patients to be discharged safely without opioid prescriptions. We have developed a proprietary sustained-release carrier, SB Gel, which can be mixed with the local anesthetic bupivacaine at the time of use and applied as an aqueous solution that forms a soft gel in the surgical site. SB Gel provides diffusion-based release of bupivacaine over multiple days and dissolves in vivo in about three weeks. In a pig skin and muscle incision model, bupivacaine-loaded SB Gel provided analgesia lasting for 120 hours. Significantly greater force at the incision was tolerated in sites receiving SB Gel + bupivacaine compared to those receiving Exparel at 24, 48, 72, 96, and 120 hours postoperatively. We now propose to complete a Phase 1 project to establish the feasibility of bupivacaine- loaded SB Gel as the best-in-class extended-release local anesthetic. In Aim 1, we will study the dose response of SB Gel + bupivacaine, compare the effectiveness of SB Gel + bupivacaine against all of the FDA-approved extended-release local anesthetics, and evaluate effects on wound healing. In Aim 2, we will evaluate safety, including systemic toxicity, systemic exposure to bupivacaine, and toxicity to muscle and peripheral nerves. Successful completion of the project will result in readiness for scaled-up manufacturing and future IND-enabling toxicology studies.