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，部分由随后受损的周围神经纤维或支配损伤组织的纤维功能障碍维持。神经纤维损伤的影响包括损伤部位和损伤周围区域神经功能的改变。某些类型的周围神经损伤引起神经瘤的发展，并伴有局部慢性疼痛，表现为异常性疼痛和痛觉过敏。约30%的神经瘤患者疼痛严重，受影响的手指、手或肢体无法进行日常生活活动，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较差。这种神经瘤疼痛的确切病理生理机制尚不清楚，尽管外周和中枢致敏已被推测。降钙素基因相关肽（CGRP）在这一过程中起关键作用。CGRP由背根神经节（DRG）的伤害感觉神经元合成，并在脊髓和周围神经末梢释放，其中肽使次级神经元致敏。外周释放CGRP的作用是多方面的，包括诱导血管舒张和巨噬细胞募集。外周神经损伤后大鼠DRG神经元中CGRP表达增加，CGRP在实验诱导的大鼠神经瘤及人神经瘤中积累。此外，在实验诱导的糖尿病神经病变中，CGRP过量释放到大鼠皮肤中。这些结果表明，CGRP合成和释放的增加至少在某些类型的神经性疼痛中是重要的，并且可能特别涉及神经瘤痛。最有效和选择性的CGRP受体拮抗剂CGRP8-37是一种大肽，不易通过常规途径递送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CGRP8-37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 DA026363）。在这项研究中，我们证明了微针给药CGRP8-37或CGRP8-37与Na+通道阻滞剂联合给药到皮肤，成功地阻断了紫外线B照射（UVB）后大鼠皮肤的神经源性炎症性疼痛。在这里提出的SBIR二期研究中，我们

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.