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: 9097142
• 负责人: Wai Hong Lo
• 金额: $ 9.79万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097142
• 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; Formulation; Gel; Health; 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; Site; Spinal Ganglia; System; Testing; Therapeutic; Time; Tissues; Translations; base; chronic pain; combat; controlled release; crosslink; cytotoxic; cytotoxicity; design; in vivo; materials science; nanoparticle; novel; novel therapeutics; painful neuropathy; response; ropivacaine; subcutaneous; systemic toxicity

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)：可注射的局部麻醉剂，可持续7天，可对慢性肌肉骨骼疼痛的治疗产生重大影响。然而，目前的方案由于需要重复给药的行动持续时间相对较短而受到限制。此外，局麻药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，我们建议开发一种新的注射止痛释放系统，持续时间长达7天，副作用最小。协同药物组合与可生物降解的水凝胶聚合物一起使用的方法已被证明可以延长神经阻滞。我们以前已经证明，由壳聚糖、罗比卡因和地塞米松组成的水凝胶系统在体内可以控制麻醉药物的释放和持续的麻醉效果。虽然该系统很有前景，但地塞米松的使用对肌肉骨骼组织来说是有问题的，这可能不适合肌肉酮体疼痛的治疗。眼镜蛇毒素(CTX)具有镇痛活性持久、不会上瘾、副作用小、价格相对低廉、可商业化等优点，被认为是一种新的止痛方案。我们的初步数据表明-CTX对成骨细胞和神经元的细胞毒作用较小。在这里，我们建议通过协同结合罗哌卡因和-CTX来开发一种扩展的局部可注射水凝胶控释系统。我们假设酶交联的壳聚糖水凝胶可以局部释放并维持罗比卡因和-CTX的释放，罗比卡因和-CTX的协同作用将有助于在最小的炎症反应下实现长达7天的止痛。我们建议通过两个特定的目标来验证这一假设：1)开发和表征罗比卡因-环磷酰胺可注射壳聚糖水凝胶作为局部控释系统，并使用细胞培养模型评价该制剂的体外生物活性。2)评价罗比卡因/环磷酰胺壳聚糖水凝胶的体内生物学性能。如果成功，这项拟议的研究将对长期局部止痛系统的临床转化产生重大影响，以实现有效的肌肉骨骼疼痛管理。

项目成果

Injectable nanocomposite analgesic delivery system for musculoskeletal pain management.

• DOI: 10.1016/j.actbio.2018.05.038
• 发表时间: 2018-07-01
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Khanal M;Gohil SV;Kuyinu E;Kan HM;Knight BE;Baumbauer KM;Lo KW;Walker J;Laurencin CT;Nair LS
• 通讯作者: Nair LS

Pain management via local anesthetics and responsive hydrogels.

• DOI: 10.4155/tde.14.95
• 发表时间: 2015-02
• 期刊: Therapeutic delivery
• 影响因子: 4.2
• 作者: Bagshaw KR;Hanenbaum CL;Carbone EJ;Lo KW;Laurencin CT;Walker J;Nair LS
• 通讯作者: Nair LS