Novel Injectable Analgesic Delivery System for Chronic Musculoskeletal Pain Manag

用于治疗慢性肌肉骨骼疼痛的新型注射镇痛输送系统

• 批准号: 8683507
• 负责人: Wai Hong Lo
• 金额: $ 17.49万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683507
• 关键词: Absence of pain sensation; Address; Adverse effects; Affect; Afferent Neurons; Analgesics; Anesthetics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biological; Biological Assay; Cell Culture Techniques; Cells; Chitosan; Chronic; Clinical; Combined Modality Therapy; Data; Development; Devices; Dexamethasone; Diffuse; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug usage; Gel; Hour; Hydrogels; In Vitro; Inflammation; Inflammatory Response; Injectable; Injection of therapeutic agent; Kinetics; Liposomes; Local Anesthetics; Local anesthesia; Microspheres; Modeling; Molecular Biology; Musculoskeletal; Musculoskeletal Pain; Nanosphere; Nerve Block; Neurons; Nociception; Operative Surgical Procedures; Osteoblasts; Pain; Pain management; Patients; Peptides; Performance; Pharmaceutical Preparations; Polymers; Property; Proteins; Rattus; Regimen; Research Personnel; Science; Site; Spinal Ganglia; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; alpha-cobratoxin; base; chronic pain; combat; controlled release; crosslink; cytotoxic; cytotoxicity; design; in vivo; nanoparticle; novel; painful neuropathy; public health relevance; response; ropivacaine; subcutaneous

DESCRIPTION (provided by applicant): Injectable local anesthetics that would last up to 7 days could have a significant impact on chronic musculoskeletal pain management. However, current formulations have been limited by their relatively short duration of action required repeated administrations. In addition, local anesthetics are often associated with systemic toxicity and local tissue site inflammatory responses. To address these issues, we propose is to develop a novel injectable analgesia delivery system lasting up to 7 days with minimum side effects. Approaches that synergistic drug combinations used in conjunction with biodegradable hydrogel polymer have been shown to prolong neural blockade. We have previously demonstrated that a hydrogel system composed of chitosan, ropivacaine and dexamethasone resulted in controlled anesthetic drug delivery and sustained anesthetic effects in vivo. Although the system is quite promising, the use of dexamethasone has been problematic to musculoskeletal tissue, this it might not be suitable for musculoskeketal pain management. Alpha cobratoxin ( -CTx) is believed to be the new regimen to combat pain with the advantages of long-lasting analgesia activity, non-addictive, minimal side effects, relatively inexpensive, an commercial availability. Our preliminary data indicated that -CTx has less cytotoxic effect to osteoblast and neurons. Here we propose to develop an extended local injectable hydrogel based controlled release system by synergistically combining ropivavaine and -CTx. We hypothesize that an enzymatically cross-linked chitosan hydrogel can locally deliver and sustain the release of ropivacaine and -CTx and that the synergistic effect of ropivacaine and - CTx will help to achieve pain relief for up to 7 days with minimal inflammatory response. We propose to test the hypothesis via two specific aims 1) To develop and characterize a ropivacaine- CTx loaded injectable chitosan hydrogel as a local control delivery system and evaluate the in vitro bioactivity of the formulation using cell culture model. 2) To evaluate the in vivo biological performance of the ropivacaine and CTx -loaded chitosan hydrogel. If successful the proposed study will have a significant impact in the clinical translation of prolonged local pain relief systems for efficient musculoskeletal pain management.

描述（由申请人提供）：可持续7天的可注射局部麻醉剂可能会对慢性肌肉骨骼疼痛管理产生重大影响。但是，当前的配方受到相对较短的行动持续时间的限制，需要重复管理。此外，局部麻醉通常与全身毒性和局部组织部位炎症反应有关。为了解决这些问题，我们建议是开发一种新型的可注射镇痛输送系统，最多可以使用7天，而副作用最小。已经证明，与可生物降解的水凝胶聚合物结合使用的协同药物组合已被证明可以延长神经阻滞。我们以前已经证明，由壳聚糖，ropivacaine和地塞米松组成的水凝胶系统可导致麻醉药物的递送，并在体内持续麻醉作用。尽管该系统非常有前途，但地塞米松的使用对肌肉骨骼组织是有问题的，但这可能不适用于肌肉珠乳痛管理。据信，α同霉素（-CTX）是应对疼痛的新方案，具有长期镇痛活性，非添加性，最小的副作用，相对便宜的商业可用性的优势。我们的初步数据表明，-CTX对成骨细胞和神经元的细胞毒性作用较小。在这里，我们建议通过协同结合ropivavaine和-ctx开发一种扩展的局部可注射水凝胶的受控释放系统。我们假设酶线交联的壳聚糖水凝胶可以在本地传递和维持Ropivacaine和-ctx的释放，并且Ropivacaine和-ctx的协同作用将有助于实现最多7天的疼痛，以减少7天的炎症反应。我们建议通过两个特定目的检验假设1）开发和表征ropivacaine-ctx载荷可注射的壳聚糖水凝胶作为局部控制输送系统，并使用细胞培养模型评估配方的体外生物活性。 2）评估ropivacaine和CTX负载的壳聚糖水凝胶的体内生物学性能。如果成功，则提出的研究将对延长局部疼痛缓解系统的临床翻译产生重大影响，以进行有效的肌肉骨骼疼痛管理。