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: 10298503
• 负责人: Leon Marcel Bellan
• 金额: $ 22.98万
• 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/10298503
• 关键词: Acute Pain; Adopted; Analgesics; Anesthetics; Behavior; Bupivacaine; Cell Culture Techniques; 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; Ultrasonography; United States; Work; addiction; chronic pain; crosslink; high risk; in vivo; innovation; interest; nile red; opioid abuse; opioid epidemic; opioid use; pain relief; programs; response; side effect; small molecule; subcutaneous

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.

概括 在美国，阿片类药物成瘾和虐待的严重程度越来越多导致增加 对更有针对性和受控方法进行疼痛管理的兴趣。特别是长时间 持续时间局部麻醉有可能同时治疗慢性和急性疼痛而没有许多 全身疗法的缺点和风险。患者本身是非常希望的 可控和非侵入性触发麻醉剂的释放来控制自己的痛苦。启用 这种能力，已经开发出了几种方法。但是，这些系统中使用的刺激 必须由复杂设备提供，该设备可以在光热，超声波中发送必要的能量 或电磁形式以触发释放。作为一个更简单的选择，我们将开发一个平台，启用 从植入的热响应聚合物凝胶中冷却触发麻醉药的释放，使得 冰或冷包在皮肤上的应用会触发长时间的疼痛缓解。这种方法利用 患者已经与暂时缓解疼痛相关的刺激，即冷却，并避免需要 复杂的设备以提供适当形式的能量以触发。 虽然注射热凝胶制剂的降解已用于可控释放 治疗分子，迄今为止，还没有探索使用冷却的概念 在注射这些配方时形成的物理交联凝胶的诱导拆卸 从室温到生理温度变暖）。我们将利用冷却引起的 物理交联的凝胶的液化，以触发凝胶中隔离的有效载荷的释放。 释放速率将通过储层周围的速率控制膜调节。我们将首先 开发适当的表征以表征该概念如何实现冷却触发的释放 体外模型药物，然后转到体内研究，以证明该平台的稳定性 在生理温度和模型有效载荷的释放下，将冰涂在 皮肤。此外，我们将表征有效载荷对镇痛肽建模的释放行为。 最后，我们将展示热响应聚合物稳定加载典型麻醉的能力， 布比卡因，当在生理温度下进行物理交联时，冷却后，慢慢释放 这种用于长时间局部麻醉的治疗性。这项研究工作的最终结果将是 开发可植入的热响应性治疗配方，可长期疼痛 冷却后通过局部麻醉的递送缓解，将冷却作为治疗的新刺激 发布策略。