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

冷却触发热敏凝胶释放麻醉剂，按需缓解疼痛

• 批准号: 10443868
• 负责人: Leon Marcel Bellan
• 金额: $ 22.96万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443868
• 关键词: Acute Pain; Adopted; Analgesics; Anesthetics; Behavior; Bupivacaine; Cells; Complex; Data; Development; Devices; Disadvantaged; Drops; Drug Delivery Systems; Drug Modelings; Electromagnetics; Encapsulated; Equipment; Extravasation; Familiarity; Formulation; Foundations; Future; Gel; Grant; Ice; Implant; In Vitro; Injectable; Injections; Knowledge; Literature; Local Anesthetics; Local anesthesia; Membrane; Modeling; Nanoporous; Nerve Block; Numbness; Opiate Addiction; Opioid; Overdose; Pain; Pain management; Patients; Peptides; Pharmaceutical Preparations; Physiological; Polymers; Procedures; Research; Risk; Rodent Model; Severities; Skin; Sports Medicine; Stimulus; System; Systemic Therapy; Technology; Temperature; Therapeutic; Tissues; Transition Temperature; United States; Work; addiction; chronic pain; crosslink; delivery vehicle; high risk; in vivo; innovation; interest; nile red; opioid abuse; opioid epidemic; opioid use; pain relief; programs; response; side effect; small molecule; subcutaneous; ultrasound

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.

总结 在美国，阿片类药物成瘾和滥用的严重程度日益增加，导致 对更有针对性和控制性的疼痛管理方法感兴趣。特别是，长期 持续局部麻醉有可能治疗慢性和急性疼痛， 系统治疗的缺点和风险。患者自己非常希望能够 可控地和非侵入性地触发麻醉剂的释放来控制他们自己的疼痛。使 已经开发了几种方法来实现这种能力;然而， 必须由复杂的设备提供，该设备可以以光热，超声， 或电磁形式来触发释放。作为一个更简单的替代方案，我们将开发一个平台， 从植入的温敏聚合物凝胶中冷却触发释放麻醉剂， 在皮肤上敷冰或冷敷会延长疼痛缓解时间。这种方法利用了 患者已经与暂时疼痛缓解相关联的刺激，即冷却，并且避免了对 复杂的装置以适当的形式输送能量用于触发。 虽然可注射热胶凝制剂的降解已经用于可控地释放 治疗分子，迄今为止还没有探索利用冷却的概念， 诱导在注射这些制剂时形成的物理交联凝胶的分解（由于 到从室温升温到生理温度）。我们将利用冷却诱导 物理交联的凝胶液化以触发隔离在凝胶内的有效载荷的释放。 释放速率将由围绕储库的速率控制膜调节。我们将首先 开发适当的配方，以表征这一概念如何使冷却触发释放 体外模型药物，然后进行体内研究，以证明该平台的稳定性 在生理温度和释放的模型有效载荷，尼罗河红，后申请冰的 皮肤此外，我们将表征镇痛肽建模的有效载荷的释放行为。 最后，我们将证明热敏聚合物稳定负载典型麻醉剂的能力， 布比卡因，当在生理温度下物理交联时， 这种治疗方法用于长时间的局部麻醉。这项研究工作的最终结果将是 开发了一种可植入的温度响应治疗制剂， 通过局部麻醉输送缓解冷却，建立冷却作为治疗的新刺激 释放战略。