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，美国大约有2600万至2700万人患有中度至重度慢性疼痛。慢性疼痛的一个关键病理生理学是神经源性炎症，它主要是由无髓鞘感觉神经元通过有害刺激激活，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）引起的。神经源性炎症涉及各种病因不明的人类疾病或综合征的病理生理学，如偏头痛、关节炎和复杂的局部疼痛综合征。动物研究表明，释放的CGRP作用于其受体，可能在神经源性硬脑膜血管舒张的病因学中起关键作用，而硬脑膜血管舒张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拮抗剂临床试验为这一理论提供了实质性的支持。目前，已确定的选择性CGRP受体拮抗剂是人a-CGRP的c端片段（hCGRP8-37）。由于hCGRP8-37不是一个小分子，因此将这种大肽递送到神经源性炎症部位是一个巨大的挑战。我们建议采用基于微针的技术，在不使用标准针头和注射器的情况下，将hCGRP8-37经皮灌注到大鼠皮肤炎症部位。与其他微针不同，我们的微针是由生物相容性水溶性“公认安全”（GRAS）材料制成的，并浸渍了待递送的生物分子，在这种情况下是hCGRP8-37。微针穿透皮肤，溶解在组织液中，同时输送生物分子。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hCGRP8-37的可溶微针贴片，并在体外制备大鼠尸体皮肤上测定微针中拮抗剂的释放动力学。2. 通过疼痛行为评估和水肿测量，评估抗cgrp微针贴片在大鼠神经源性炎症性疼痛模型中的有效性。本一期项目的目的是验证可溶微针贴片能够以缓慢持续的扩散方式将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的痛觉过敏和水肿的假设。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。最近的调查显示，在美国大约有2600万到2700万人患有中度到重度疼痛。疼痛的主要原因之一是神经源性炎症，它与慢性疼痛综合征如偏头痛、关节炎和复杂的局部疼痛综合征有关。动物研究表明，疼痛与CGRP释放有关，可通过持续向炎症部位提供抗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症性疼痛。

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.