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

描述(由申请人提供)： 布比卡因是一种局部麻醉剂，通常用于治疗择期骨科手术后的疼痛。患者在手术前接受局部麻醉，阻断神经结构，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间隙的导管持续释放麻醉剂，以及关节内留置导管以预定的速度连续释放局部麻醉剂48小时。在庞大的止痛药宝库中加入局部麻醉药，以控制术后疼痛，有助于减少麻醉剂的使用和滥用。然而，这些方式有相关的并发症，包括麻醉不充分，患者术后抗凝的硬膜外出血，关节内导管对外部环境开放的感染。我们建议使用新的溶胶凝胶技术进行布比卡因的时间控制释放。药物分子被结合到纳米孔通道中，并通过渗透到这些孔中的水相扩散释放。溶胶-凝胶可以合成成整体或10微米的颗粒。在这一阶段，布比卡因已经成功地被结合到溶胶凝胶中，并表现出良好的逃逸特性。初步确定了不同工艺参数下的体外释药速率。体内可行性研究表明，通过植入溶胶凝胶-布比卡因颗粒给药的布比卡因存在长达5至7天的剂量依赖效应。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颗粒释放的体内测试，这三个模型此前已被用于研究疼痛控制。它们包括广泛使用的Brennan切口痛模型和两个与骨科条件相关的模型，即神经病理性疼痛的颈根神经损伤模型和坐骨神经阻滞模型。本研究的研究内容如下：(1)布比卡因体外释放度的优化。(2)体内实验：建立(A)不同剂型的溶胶凝胶中布比卡因的体内外释放曲线之间的关系，以及(B)溶胶凝胶/布比卡因的有效剂量和给药剂量与行为反应的关系。(3)体内阶段II，现在将利用体内研究I的结果进行更大规模的实验，使用三种模型中的每一种，以实现两次剂量的统计学意义。在这项二期研究中，除了测试行为反应外，我们还将在特定时间采集血液样本，以确定布比卡因的全身浓度，以建立剂量关系。所有的数据结合在一起，即体外释放的数据，使用现有疼痛治疗模型从两个阶段的体内研究中获得的数据，以及单独和在世界各地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我们的所有数据，但在这里提出的资金周期内，我们还不会开展这项工作。对于退伍军人事务部医学中心接受择期骨科手术的患者群体来说，缩短住院时间、减少术后麻醉剂的使用以及提高参与物理治疗和达到康复目标的意愿是实现良好结果的关键。这项建议解决了这些问题，符合医疗保健市场以精简成本效益和减少医疗保健支出为目标的大趋势

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