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

溶胶凝胶定时释放局部麻醉剂用于术后疼痛控制

• 批准号: 8838118
• 负责人: JONATHAN Peter GARINO
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838118
• 关键词: Address; Analgesics; Anesthetics; Behavioral; Blood specimen; Bupivacaine; Catheters; Cervical; Clinical; Clinical Research; Cytoplasmic Granules; Data; Diffusion; Dose; Drug Formulations; Environment; Epidural Anesthesia; Exhibits; Feasibility Studies; Funding; Gel; Goals; Health Expenditures; Healthcare Market; Hemorrhage; Hour; In Vitro; Indwelling Catheter; Infection; Injection of therapeutic agent; Laboratories; Length of Stay; Local Anesthetics; Medical center; Modality; Modeling; Narcotics; Nerve Block; Operative Surgical Procedures; Orthopedic Surgery procedures; Orthopedics; Outcome; Pain; Pain management; Patients; Pharmaceutical Preparations; Phase; Physical therapy; Plant Roots; Population; Postoperative Period; Process; Rattus; Research; Site; Staging; Structure; Study models; Technology; Testing; Time; Vertebral column; Veterans; Work; aqueous; base; behavior test; controlled release; cost; design; epidural space; implantation; in vivo; meetings; nanosized; nerve injury; nerve supply; novel; painful neuropathy; particle; patient population; phase 2 study; response; sciatic nerve; trend; willingness

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

描述（由申请人提供）： 布比维亚人是一种局部麻醉剂，通常用于治疗选度骨科手术后疼痛。患者经历了术前的局部麻醉神经结构，这些神经结构为手术部位提供神经。其他选择包括在手术部位进行麻醉注射，使用腰椎放置在硬膜外空间中的导管连续释放药物和关节内留置导管，该导管以预定的速度连续释放局部麻醉48小时。将局部麻醉剂添加到大量的止痛药物中，以控制后疼痛，这有助于减少麻醉药的使用和滥用。然而，这些方式具有相关的并发症，包括麻醉块不足，在后期抗凝的患者的硬膜外出血，以及对外部环境开放的关节内导管的感染。 我们建议将新颖的Sol Gel技术用于布比卡因的时间释放。药物分子掺入纳米化孔通道中，并通过渗透到这些孔中的水相扩散而释放。溶胶凝胶可以合成为整体，也可以作为10微米颗粒合成。在此阶段，布比卡因已成功地纳入SOL凝胶中，并表现出良好的露出特征。已经确定了各种处理参数集的维特罗释放速率的初步定量。体内可行性研究表明，布比卡因通过植入溶胶凝胶 - 布比卡因颗粒的剂量依赖性作用，最多可达5至7天。我们建议优化体外分析，然后在三种大鼠模型中对颗粒中布比卡因释放的体内测试进行体内测试，这些模型先前已被用于研究疼痛控制。它们包括广泛使用的切口疼痛的Brennan模型，以及与骨科条件相关的两个模型，即神经性疼痛的宫颈根神经损伤模型和坐骨神经阻滞模型。 这项研究的研究组成部分如下：（1）优化布比卡因的体外释放曲线。 （2）在体内I阶段（a）在各种配方的溶胶凝胶中的体外和体内释放曲线之间的关系，以及（b）有效剂量以及剂量的溶胶凝胶/bupivivacaine剂量之间的关系以及行为反应。 （3）在体内II期中，体内研究的结果现在将使用三个模型中的每一个，用于更大范围的实验，以用两种剂量实现统计显着性。在这项2阶段的研究中，除了测试行为反应外，我们还将在特定时间收集血液样本，以确定布比卡因的全身浓度以建立剂量关系。 所有数据结合在一起，即体外释放的数据，使用现有模型研究疼痛治疗的两个阶段研究获得的数据，以及分别获得的数据以及在全球其他实验室中获得的数据将构成设计随后的临床研究的基础。尽管根据预期的临床用途，我们将分析所有数据，但我们尚未在此处提出的资金周期中进行这项工作。 对于退伍军人事务中心医疗中心接受选修骨科手术的患者人群，医院较短的住院问题，术后麻醉后的使用量减少以及越来越多的意愿参加物理治疗和实现康复目标对于获得良好的结果至关重要。该提案解决了这些问题，并符合医疗市场的总体趋势，以瞄准简化的成本效率和减少医疗保健支出