Development of a heated transdermal microneedle naloxone patch as an innovative treatment for opioid overdose

项目总结/摘要 阿片类药物过量流行病正在以大规模伤亡事件的水平杀死美国人-卡特里娜飓风造成死亡 1，577人，但仅在加州，2018年阿片类药物过量的死亡人数就为5，348人。合成，更多 芬太尼及其衍生物等强效阿片类药物正在进一步增加死亡人数。纳洛酮（NLX）， 阿片类拮抗剂，是阿片类药物过量的解毒剂。NLX的工作原理是将阿片分子从 受体，最终逆转呼吸抑制。NLX静脉内（IV）给药， 肌内（IM）、皮下（SC）或鼻内给药。不幸的是，所有市售剂型 具有显著的缺点，使得它们对于院前环境具有挑战性。最值得注意的是，NLX遭受 血浆半衰期非常短，如果药物中存在非常大量的阿片类药物，则存在过量复发的风险。 等离子体这导致需要重复给予NLX剂量（称为“救援”剂量）以防止缺氧， 并且该缺点为所有递送途径所共有并且变得越来越普遍。额外 挑战包括需要使用针头/注射器进行IV/IM/SC输送，这在这种情况下非常危险 鼻内给药不是一致有效的，并且在潜在的好斗患者中是禁忌的。 鼻内损害的背景下，这是经常看到与使用其他非法物质。在这项研究中，我们建议 为了克服目前NLX剂型的缺点， 具有微针的透皮贴剂。长期目标是减少院前阿片类药物过量死亡 通过开发新的透皮NLX剂型。目的是通过以下方式快速交付NLX 皮肤，目的是达到一致的和治疗相关的药物浓度，而无需抢救 剂量该提案的中心假设是NLX将通过表皮快速持续吸收 在皮肤温度升高与皮肤组织的收缩速率和程度之间存在正相关性。 NLX渗透。该贴剂将包括3层：1）溶解微针，2）透皮NLX凝胶，和3）微针凝胶。 加热层每一层都具有特定的功能，具有产生NLX皮肤渗透的综合效果 可以达到治疗阿片类药物过量的血浆水平。溶解NLX微针将 当它们溶解时立即开始递送NLX，同时还产生微孔以允许透皮NLX 从凝胶中释放。贴剂贴敷后，凝胶将通过微孔输送NLX至少2小时 应用程序.加热层将在暴露于空气时迅速产生热量，增加皮肤温度， 从而增加NLX吸收的速率和程度。该贴片旨在仅在一个步骤中应用。 在目标1中，我们将在体外优化每个贴片层，以满足预定的里程碑，从而提供类似的递送 IM NLX交付的参数。在目标2中，将在药代动力学研究中对贴剂层进行体内测试， 豚鼠在融资期结束时，我们预计将有一个透皮NLX原型贴剂， 准备快速进入IND申请和初步人体研究。

PROJECT SUMMARY/ABSTRACT The opioid overdose epidemic is killing Americans at the level of a mass casualty event – Hurricane Katrina killed 1,577 people but the death toll from opioid overdose in 2018 in California alone was 5,348. Synthetic, more potent opioids such as fentanyl and its derivatives are further increasing the numbers of deaths. Naloxone (NLX), an opioid antagonist, is the antidote for opioid overdose. NLX works by displacing opioid molecules from receptors in the body, ultimately reversing the respiratory depression. NLX is administered intravenously (IV), intramuscularly (IM), subcutaneous (SC), or intranasally. Unfortunately all commercially available dosage forms have significant shortcomings, making them challenging for pre-hospital settings. Most notably, NLX suffers from a very short plasma half-life, presenting a risk of overdose relapse if there is a very large amount of opioid in the plasma. This results in need for repeated NLX doses to be given (known as “rescue” doses) to prevent hypoxia, and this disadvantage is shared by all routes of delivery and is becoming increasingly common. Additional challenges include the need for use of needles/syringes with IV/IM/SC delivery, which is very risky in the context of a potentially combative patient; intranasal delivery is not uniformly effective, and is contraindicated in the context of intranasal damage that is often seen with use of other illicit substances. In this research we propose to overcome the shortcomings of current NLX dosage forms through development of a novel self-heating transdermal patch with microneedles. The long-term goal is to decrease pre-hospital opioid overdose deaths through development of the novel transdermal NLX dosage form. The intent is to deliver NLX quickly through the skin, aiming to achieve consistent and therapeutically relevant drug concentrations without need for rescue doses. The central hypothesis of this proposal is that NLX will rapidly and continuously absorb through epidermal micropores, and a positive correlation will exist between elevated skin temperature and the rate and extent of NLX permeation. The patch will include 3 layers: 1) dissolving microneedles, 2) a transdermal NLX gel, and 3) a heating layer. Each layer fulfills a specific function, with the combined effect of producing NLX skin permeation that can reach plasma levels appropriate for treating opioid overdose. Dissolving NLX microneedles will immediately start to deliver NLX as they dissolve, while also creating micropores to allow transdermal NLX delivery from the gel. The gel will deliver NLX through the micropores for a minimum of 2 hrs after patch application. The heating layer will rapidly generate heat upon air exposure, increasing skin temperature and thereby increasing the rate and extent of NLX absorption. The patch is intended to be applied in just one step. In Aim 1 we will optimize each patch layer in vitro to meet predetermined milestones to provide similar delivery parameters to IM NLX delivery. In Aim 2 the patch layers will be tested in vivo in pharmacokinetic studies in guinea pigs. At the end of the funding period we expect to have a transdermal NLX prototype patch that will be ready to quickly move into IND filing and preliminary human studies.