Novel Injectable Analgesic Delivery System for Chronic Musculoskeletal Pain Manag

描述（由申请方提供）：可持续7天的可注射局部麻醉剂可能对慢性肌肉骨骼疼痛管理产生显著影响。然而，目前的制剂受到其需要重复施用的相对较短的作用持续时间的限制。此外，局部麻醉剂通常与全身毒性和局部组织部位炎症反应相关。为了解决这些问题，我们建议开发一种新的可注射镇痛给药系统，持续长达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结合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，罗哌卡因和地塞米松组成的水凝胶系统导致在体内控制麻醉药物的输送和持续的麻醉效果。虽然该系统是相当有前途的，地塞米松的使用一直是肌肉骨骼组织的问题，这可能不适合肌肉骨骼疼痛管理。α眼镜蛇毒素（-CTx）被认为是对抗疼痛的新方案，具有持久镇痛活性、非成瘾性、副作用最小、相对便宜、商业可用性的优点。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，我们建议开发一种扩展的局部注射水凝胶为基础的控制释放系统，协同结合罗哌卡因和-CTx。我们假设酶交联的壳聚糖水凝胶可以局部递送并维持罗哌卡因和-CTx的释放，并且罗哌卡因和- CTx的协同效应将有助于实现疼痛缓解长达7天，炎症反应最小。我们提出通过两个具体目标来测试该假设1）开发和表征作为局部控制递送系统的罗哌卡因- CTx负载的可注射壳聚糖水凝胶，并使用细胞培养模型评价制剂的体外生物活性。2)评价罗哌卡因和环磷酰胺复合壳聚糖水凝胶的体内生物学性能。如果成功的话，拟议的研究将对长期局部疼痛缓解系统的临床转化产生重大影响，以有效地进行肌肉骨骼疼痛管理。

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.