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，美国约有2600万至2700万人患有中度至重度慢性疼痛。慢性疼痛的关键病理生理学是神经源性炎症，其主要由无髓鞘感觉神经元通过伤害性刺激的激活和随后从这些伤害性神经元的外周末梢释放神经肽如降钙素基因相关肽（CGRP）和P物质（SP）引起。神经源性炎症与各种病因不明的人类疾病或综合征的病理生理学有关，如偏头痛、关节炎和复杂区域疼痛综合征。动物研究表明，释放的CGRP作用于其受体可能是神经源性硬脑膜血管舒张的病因学关键，被认为是偏头痛和其他神经血管疼痛产生的关键环节。最近的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，建立的选择性CGRP受体拮抗剂是人α-CGRP的C-末端片段（hCGRP 8 -37）。由于hCGRP 8 -37不是小分子，因此将这种大肽递送至神经源性炎症部位代表了巨大的挑战。我们建议使用基于微针的技术将hCGRP 8 -37经皮输注到大鼠皮肤区域的发炎部位，而不使用标准的针头和注射器。与其他微针不同，我们的微针由生物相容的水溶性“公认安全”（GRAS）材料制成，并浸渍有待递送的生物分子，在这种情况下为hCGRP 8 -37。微针穿透皮肤并在递送生物分子的同时溶解在间质液中。因此，我们将利用这种新的药物输送技术和我们的合作者斯坦福大学的大卫约曼斯博士深入疼痛研究的专业知识，开发和测试一种创新的抗CGRP微针贴片。我们的目标是-1。制备掺入hCGRP 8 -37的可溶性微针贴剂，并使用体外急性制备的大鼠尸体皮肤测定拮抗剂从微针的释放动力学。2.使用疼痛行为评估和水肿测量评价抗CGRP微针贴片在大鼠神经源性炎性疼痛模型中的有效性。该I期项目的目的是测试以下假设：可溶性微针贴片可以以缓慢持续扩散的方式将CGRP受体拮抗剂递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中的痛觉过敏和水肿。我们的最终目标是开发安全，有效和方便的微针贴片，以阻断外周CGRP受体介导的病理性，神经源性疼痛条件下发生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。疼痛的主要原因之一是神经源性炎症，其与慢性疼痛综合征如偏头痛、关节炎和复杂区域疼痛综合征相关。动物研究表明，疼痛与CGRP释放有关，这可以通过向炎症部位持续供应抗CGRP来预防。我们建议开发一种创新的抗CGRP贴片，用于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.