Timed-release of Local Anesthetic from Sol Gels for Post-Op Pain Control

描述（由申请人提供）： 布比卡因是一种常用于治疗择期骨科手术后疼痛的局部麻醉剂。患者在术前接受神经结构的局部麻醉阻滞，为手术部位提供神经支配。其他选择包括在手术部位注射麻醉剂，使用通过腰椎放置在硬膜外腔中的导管以连续释放药剂，以及关节内留置导管以预定速率连续释放局部麻醉剂48小时。将局部麻醉剂添加到用于术后疼痛控制的大量止痛药中有助于减少麻醉剂的使用和滥用。然而，这些模式具有相关的并发症，包括麻醉阻滞不足、术后抗凝患者的硬膜外出血以及开放至外部环境的关节内导管的感染。 我们建议使用新的溶胶-凝胶技术的时间控制释放布比卡因。药物分子被掺入纳米尺寸的孔通道中，并通过渗透到这些孔中的水相的扩散而释放。溶胶凝胶可以合成为整料或10微米颗粒。在这个阶段，布比卡因已成功掺入溶胶凝胶中并表现出良好的洗脱特性。已经确定了各组加工参数的体外释放速率的初步定量。体内可行性研究表明，通过植入溶胶凝胶-布比卡因颗粒施用的布比卡因的剂量依赖性效应存在长达5至7天。我们建议优化体外分析，然后在三个大鼠模型中进行布比卡因从颗粒中释放的体内测试，这些大鼠模型先前已被用于研究疼痛控制并得到验证。它们包括广泛使用的Brennan切口疼痛模型，以及两种与矫形条件相关的模型，即神经性疼痛的颈根神经损伤模型和坐骨神经阻滞模型。 本研究的主要内容如下：（1）布比卡因体外释药曲线的优化。(2)体内阶段I，以建立（a）布比卡因从各种制剂的溶胶凝胶的体外和体内释放曲线之间的关系，和（B）溶胶凝胶/布比卡因的有效剂量和施用剂量与行为反应之间的关系。(3)体内II期，其中体内研究I的结果现在将用于使用三种模型中的每一种进行更大规模的实验，以在两种剂量下达到统计学显著性。在这项II期研究中，除了测试行为反应外，我们还将在特定时间采集血样，以确定布比卡因的全身浓度，从而建立剂量关系。 所有数据组合，即体外释放数据、使用现有模型研究疼痛治疗的两阶段体内研究获得的数据以及单独获得的数据和在全球其他实验室获得的数据，将构成设计后续临床研究的基础。尽管我们将根据预期的临床用途分析所有数据，但在本文提出的资助周期内，我们尚未开展这项工作。 对于接受择期骨科手术的退伍军人事务医疗中心患者人群，缩短住院时间，减少术后麻醉剂使用，以及增加参与物理治疗和实现康复目标的意愿对于获得良好结果至关重要。这项建议旨在解决这些问题，并符合医疗保健市场的总体趋势，即以精简成本效益和减少医疗保健支出为目标

DESCRIPTION (provided by applicant): Bupivaciane is a local anesthetic commonly used for the treatment of pain following elective orthopaedic surgery. Patients undergo pre-operative local anesthetic blocks of nerve structures that provide innervation to the operative site. Other options include anesthetic injection at the site of surgery, use of a catheter placed in the epidural space through the lumbar spine for continuous release of the agent and intra- articular indwelling catheters that release local anesthetic continuously for 48 hours at a pre-determined rate. Adding local anesthetics to the vast armamentarium of pain medications for post-op pain control has helped decrease the amount of narcotic use and abuse. However, these modalities have associated complications including inadequacy of the anesthetic block, epidural bleeds in patients that are anti-coagulated in the post-op period, and infection for intra-articular catheters open to the external environment. We propose the use of the novel sol gel technology for the time controlled release of Bupivacaine. Drug molecules are incorporated in nanosized pore channels and are released by diffusion through the aqueous phase that penetrates into these pores. The sol gels can be synthesized as monoliths or as 10 micrometer granules. At this stage, Bupivacaine has been successfully incorporated into the sol gels and exhibits a favorable elusion profile. Preliminary quantification of the in-vitro release rate for various sets of processing parameters has been determined. In vivo feasibility studies have indicated that a dose-dependent effect of bupivacaine administered via implantation of sol gel - bupivacaine particles exists up to 5 to 7 days. We propose to optimize the in vitro analysis and then conduct in vivo testing of the release of Bupivacaine from granules in three rat models, which have previously been used and validated for studying pain control. They include the widely used Brennan model of incisional pain, and two models relevant to orthopaedic conditions, namely a cervical root nerve injury model of neuropathic pain and a sciatic nerve block model. The research components of this study are as follows: (1) Optimization of in vitro release profile of Bupivacaine. (2) In vivo phase I to establish (a) the relationship between the in vitro and in vivo release profiles of bupivacaine from sol gels of various formulations, and, (b) the effective doses and the relationship among the administered doses of sol gel/bupivacaine and the behavioral response. (3) In vivo phase II in which the results of in vivo study I will now be used to perform experimentation on a larger scale, using each of the three models, in order to achieve statistical significance with two doses. In this Phase 2 study, in addition to testing the behavioral response, we will also collect the blood samples at specific times to determine systemic concentrations of bupivacaine to establish a dosing relationship. All data combined, i.e. the data of the in vitro release, the data obtained from the two phase in vivo studies using existing models for studying pain treatment, as well as data obtained separately and in other laboratories worldwide will then form the basis for designing the subsequent clinical study. Although we will analyze all our data in view of the intended clinical use, we will not yet undertake this work during the funding cycle proposed here. For the Veterans Affairs Medical Center patient population undergoing elective Orthopaedic surgery, the issues of shorter hospital stay, decreased post-operative narcotic usage, and increasing willingness to participate in physical therapy and meet rehab goals are crucial to attaining good outcomes. This proposal addresses these issues and is in line with the general trend of the healthcare market in targeting streamlined cost efficiency and decreasing health care expenditures