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

基本信息

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
项目类别：
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

项目摘要

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.

概括美国各地阿片类药物成瘾和滥用日益严重，导致阿片类药物成瘾和滥用现象日益严重对更有针对性和可控的疼痛管理方法感兴趣。特别是长时间持续时间的局部麻醉有可能治疗慢性和急性疼痛，而无需进行多次治疗。全身治疗的缺点和风险。患者本人非常希望能够可控且非侵入性地触发麻醉剂的释放来控制自己的疼痛。启用对于这种能力，已经开发了几种方法；然而，这些系统中使用的刺激，必须由能够以光热、超声波、或电磁形式来触发释放。作为更简单的替代方案，我们将开发一个平台，使冷却触发从植入的热响应聚合物凝胶中释放麻醉剂，使得将冰块或冰袋敷在皮肤上可以长时间缓解疼痛。这种方法利用了患者已经将刺激与暂时缓解疼痛（即冷却）联系在一起，并且避免了需要复杂的装置以适当的形式传递能量以进行触发。虽然可注射热凝胶制剂的降解已被用于可控释放治疗分子，迄今为止还没有探索利用冷却的概念注射这些制剂后形成的物理交联凝胶的诱导分解（由于从室温升温至生理温度）。我们将利用冷却诱导物理交联凝胶的液化以触发凝胶内隔离的有效负载的释放。释放速率将由储库周围的速率控制膜调节。我们首先会开发适当的配方来描述这个概念如何实现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下，并在冰敷到模型上时释放模型有效载荷尼罗红皮肤。此外，我们将表征模拟镇痛肽的有效负载的释放行为。最后，我们将展示热敏聚合物稳定负载典型麻醉剂的能力，布比卡因在生理温度下发生物理交联，冷却后缓慢释放这种疗法适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可提供持久疼痛的可植入热响应治疗制剂通过冷却后局部麻醉剂的释放来缓解症状，将冷却作为治疗的新刺激发布策略。