Microneedle patches deliver a CGRP antagonist for neurogenic inflammatory pain

描述(由申请人提供)：最近的调查表明，在美国大约有2600万到2700万人患有中度到重度的慢性疼痛。慢性疼痛的一个重要病理生理机制是神经源性炎症，它主要是由无髓感觉神经元在伤害性刺激下被激活并随后从这些伤害性神经元的外周末端释放神经肽如降钙素基因相关肽(CGRP)和P物质(SP)引起的。神经源性炎症与多种病因不明的人类疾病或综合征的病理生理有关，如偏头痛、关节炎和复杂的区域疼痛综合征。动物研究表明，作用于其受体的CGRP释放可能在神经源性硬脑膜血管扩张的病因学中起关键作用，而神经源性硬脑膜血管扩张被认为是偏头痛和其他神经血管疼痛的关键环节。最近对CGRP拮抗剂的临床试验为这一理论提供了实质性的支持。目前已建立的选择性CGRP受体拮抗剂是人α-CGRP的C端片段(hCGRP8-37)。由于hCGRP8-37不是一个小分子，将这个大的多肽输送到神经源性炎症部位是一个巨大的挑战。我们建议使用一种基于微针的技术，在不使用标准针头和注射器的情况下，将hCGRP8-37经皮注入大鼠皮肤区域的炎症部位。与其他微针不同的是，我们的微针是由生物兼容的可溶于水的“公认为安全的”(GRAS)材料制成的，并浸透了即将交付的生物分子，在这种情况下是hCGRP8-37。微针穿透皮肤并溶解在间质液体中，同时传递生物分子。因此，我们将利用这一新颖的药物输送技术和我们的合作者斯坦福大学的David Yeomans博士深入的疼痛研究专业知识，开发和测试一种创新的抗CGRP微针贴片。我们的具体目标是：1.制备含有hCGRP8-37的可溶性微针贴剂，并用急性制备的大鼠身体皮肤测定微针中拮抗剂的体外释放动力学。2.通过疼痛行为评估和水肿量测量，评价抗降钙素基因相关肽微针贴剂在大鼠神经源性炎性疼痛模型中的作用。本项目第一阶段的目的是验证可溶微针贴片能够以缓慢的持续扩散方式将CGRP受体拮抗剂运送到神经源性炎症部位，从而阻断辣椒素神经源性炎症大鼠模型的痛觉过敏和水肿症。我们的最终目标是开发安全、有效和方便的微针贴片来阻断在病理性、神经源性疼痛条件下发生的外周CGRP受体介导的伤害性和炎症反应。最近的调查表明，美国约有2600万至2700万人患有中度至重度疼痛。引起疼痛的主要原因之一是神经源性炎症，它与偏头痛、关节炎和复杂的区域性疼痛综合征等慢性疼痛综合征有关。动物研究表明，疼痛与CGRP的释放有关，这可以通过持续向炎症部位供应抗CGRP来预防。我们建议开发一种创新的抗CGRP贴片来治疗神经源性炎性疼痛。

DESCRIPTION (provided by applicant): Recent surveys indicate that approximately 26 - 27 million individuals in the US suffer from moderate to severe chronic pain. A key pathophysiology of chronic pain is neurogenic inflammation, which is primarily elicited by activation of unmyelinated sensory neurons through noxious stimuli and the subsequent release of neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) from the peripheral endings of these nociceptive neurons. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases or syndromes with uncertain etiology, such as migraines, arthritis and complex regional pain syndrome. Animal studies suggest that released CGRP acting at its receptors may be critical in the etiology of neurogenic dural vasodilation, thought to be a critical link in the generation of migraine and other neurovascular pain. Recent clinical trials with a CGRP antagonist provide substantive support for this theory. Currently, the established selective CGRP receptor antagonist is the C-terminal fragment of the human a-CGRP (hCGRP8-37). Since hCGRP8-37 is not a small molecule, the delivery of this large peptide to neurogenic inflammatory sites represents a great challenge. We propose to use a microneedle-based technology to transdermally infuse hCGRP8-37 into an inflamed site of skin area of rats without the use of a standard needle and syringe. Unlike other microneedles, our microneedles are made of biocompatible water-dissolving "generally recognized as safe" (GRAS) materials and impregnated with the biomolecule to be delivered, in this case hCGRP8-37. The microneedles penetrate the skin and dissolve in the interstitial fluid while delivering the biomolecule. Thus, we will take advantage of this novel drug delivery technology and the in-depth pain research expertise from our collaborator, Dr. David Yeomans at Stanford University, to develop and test an innovative anti-CGRP microneedle patch. Our Specific Aims are to - 1. Fabricate the dissolvable microneedle patch incorporating hCGRP8-37 and determine the antagonist release kinetics from the microneedles using acutely prepared rat cadaver skin in vitro. 2. Evaluate the effectiveness of the anti-CGRP microneedle patch in a neurogenic inflammatory pain model in rats using pain behavior assessments and oedema measurements. The objective of this Phase I project is to test the hypothesis that the dissolvable microneedle patch can deliver the CGRP receptor antagonist in a slow sustained diffusion manner into neurogenically inflamed sites, and consequently block hyperalgesia and oedema in the capsaicin neurogenic inflammation rat model. Our ultimate goal is to develop safe, effective and convenient microneedle patches to block peripheral CGRP receptor-mediated nociceptive and inflammatory responses that occur under pathologic, neurogenic pain conditions. Recent surveys indicate that approximately 26 - 27 million individuals in the US suffer from moderate to severe pain. One of major causes of pain is neurogenic inflammation which is associated with chronic pain syndromes such as migraines, arthritis and complex regional pain syndrome. Animal studies suggest that the pain is related to CGRP release, which can be prevented by a sustained supply of anti-CGRP to the inflammation sites. We propose the development of an innovative anti-CGRP patch for the treatment of neurogenic inflammatory pain.