Treat Neuropathic Pain with Dissolvable Microneedles Containing Anti-CGRP Peptide

描述（由申请人提供）：神经性疼痛是一种复杂的慢性疼痛状态，通常由组织损伤引发，并部分由受损外周神经纤维或支配该受损组织的纤维的后续功能障碍维持。神经纤维损伤的影响包括损伤部位和损伤周围区域的神经功能变化。某些类型的周围神经损伤导致神经瘤的发展，并伴有表现为异常性疼痛和痛觉过敏的局部慢性疼痛。大约30%的这些神经瘤变得足够疼痛，以至于受影响的手指，手或肢体被排除在日常生活活动之外，患者无法完成日常任务。神经瘤疼痛特别难以治疗，并且通常对目前的神经性疼痛治疗反应不佳。虽然推测是外周和中枢致敏，但对这种神经瘤疼痛的确切病理生理机制知之甚少。降钙素基因相关肽（CGRP）似乎在这个过程中是至关重要的。CGRP由背根神经节（DRG）的伤害感受感觉神经元合成，并在脊髓中释放，其中肽使次级神经元敏感，并从外周神经末梢释放。CGRP在外周释放的影响是多方面的，包括诱导血管舒张和巨噬细胞募集。周围神经损伤后，CGRP在大鼠DRG神经元中的表达增加，并且CGRP在大鼠和人类神经瘤中的实验诱导的神经瘤中积累。此外，在实验诱导的糖尿病神经病变中证明了CGRP向大鼠皮肤中的过度释放。这些结果表明，CGRP合成和释放的增加是重要的，至少在某些类型的神经性疼痛，并可能特别涉及神经瘤疼痛。最有效和选择性的CGRP受体拮抗剂，CGRP 8 -37，是一个大的肽，不能很容易地通过普通途径传递到神经源性炎症部位。为了克服这一问题，我们开发并利用了创新的可溶解CGRP 8 -37微针技术，并在SBIR I期支持下完成了其镇痛潜力的可行性研究（R43 DA 026363）。在这项研究中，我们证明了将CGRP 8 -37或CGRP 8 -37和Na+通道阻断剂的组合微针递送至皮肤，成功地阻断了大鼠皮肤的紫外线B照射（UVB）后的神经源性炎性疼痛。在SBIR第二阶段研究中，我们 将重点评价两种临床适用的神经病理性疼痛动物模型-备用神经损伤模型和胫神经瘤移位模型中的微针疗效。为了开发IND应用，我们还将研究微针在皮肤敏感性高于大鼠的家兔中的安全性。具体目标如下：1.测试CGRP 8 -37微针贴片在两种大鼠神经性疼痛模型中的功效：区域性疼痛的坐骨神经损伤模型和更局部化的神经性模型，胫骨神经瘤易位模型。2.在大鼠和家兔中研究微针经皮给药后的局部皮肤毒性，并在大鼠中评价CGRP 8 -37全身给药后的毒性。3.检查优化微针贴片生产工艺的方法，为未来的IND研究做准备。该II期项目如果成功，将为IND启动研究提供基于证据的通过/不通过决定，该IND启动研究可导致在该II期SBIR项目的竞争性更新支持下，在志愿者和患者中进行CGRP 8 -37微针的首次人体试验。

DESCRIPTION (provided by applicant): Neuropathic pain is a complex, chronic pain state that is usually initiated by tissue injury and maintained, in part, by subsequent dysfunction of damaged peripheral nerve fibers or fibers that innervate that injured tissue. The impact of nerve fiber damage includes a change in nerve function both at the site of injury and areas around the injury. Certain types of peripheral nerve damage cause the development of neuromas with associated localized chronic pain manifested as allodynia and hyperalgesia. Approximately 30% of these neuromas become sufficiently painful that the affected digit, hand or limb becomes excluded from activities of daily living and the patient is unable to complete routine tasks. Neuroma pain is particularly difficult to treat, and generally responds poorly to current neuropathic pain treatments. The exact pathophysiology of this neuroma pain is poorly understood, though peripheral and central sensitization has been speculated. Calcitonin Gene-Related Peptide (CGRP) appears to be critical in this process. CGRP is synthesized by nociceptive sensory neurons of dorsal root ganglia (DRG) and released both in the spinal cord where the peptide sensitizes secondary neurons, and from peripheral nerve endings. The effects of CGRP release in the periphery are multifaceted, including induction of vasodilation and macrophage recruitment. Expression of CGRP increases in the DRG neurons of rats after peripheral nerve injury and CGRP accumulates in experimentally-induced neuromas in rats as well as in human neuromas. Furthermore, excessive release of CGRP into the skin of rats was demonstrated in experimentally-induced diabetic neuropathy. These results suggest that increases in CGRP synthesis and release are important in at least some types of neuropathic pain and may specifically be involved in neuroma pain. The most potent and selective CGRP receptor antagonist, CGRP8-37, is a large peptide and cannot be easily delivered to neurogenic inflammatory sites by common routes. To overcome this problem, we have developed and utilized innovative dissolvable CGRP8-37 microneedle technology and completed a feasibility study of their analgesic potential with SBIR Phase I support (R43 DA026363). In this study, we demonstrated that microneedle delivery of CGRP8-37 or a combination of CGRP8-37 and a Na+ channel blocker to the skin, successfully blocked neurogenic inflammatory pain after ultraviolet B irradiation (UVB) of the skin of rats. In the SBIR Phase II studies proposed here, we will focus on evaluation of microneedle efficacy in two clinically applicable animal models of neuropathic pain - the spared nerve injury model and the tibial neuroma transposition model. Toward the development of an IND application, we will also investigate the microneedle safety in rabbits which have higher skin sensitivity than rats. The Specific Aims are as follows: 1. Test the efficacy of CGRP8-37 microneedle patches in two rat neuropathic pain models: the Spared Nerve Injury model of regional pain and a more localized neuropathic model, the Tibial Neuroma Transposition model. 2. Investigate local dermal toxicity following the transdermal application of microneedles in rats and rabbits, and evaluate toxicity following systemic administration of CGRP8-37 in rats. 3. Examine means of optimizing manufacturing processes of microneedle patches in order to prepare for future IND studies. This Phase II project, if successful, will provide an evidence-based go/no go decision toward IND enabling studies that can lead to first-in-human testing of CGRP8-37 microneedles in volunteers and patients supported by competitive renewal of this Phase II SBIR project.