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

开发加热透皮微针纳洛酮贴片作为阿片类药物过量的创新治疗方法

• 批准号: 10351624
• 负责人: Nicole K Brogden
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351624
• 关键词: Address; Air; American; Antidotes; Benchmarking; California; Caring; Cause of Death; Cavia; Cessation of life; Clinical; Data; Detection; Development; Disadvantaged; Dosage Forms; Dose; Drug Kinetics; Effectiveness; Ensure; Epidemic; Event; Exposure to; Fentanyl; First Aid; Funding; Gel; Geriatrics; Goals; Half-Life; Health Personnel; Heating; Hospitals; Human; Hurricane; Hypoxia; In Vitro; Individual; Ingestion; Intramuscular; Intravenous; Louisiana; Medical; Methods; Naloxone; Needles; Needlestick Injuries; Opioid; Opioid Antagonist; Overdose; Patients; Pediatrics; Persons; Pharmaceutical Preparations; Plasma; Positioning Attribute; Pre-hospital setting; Pregnancy; Preparation; Property; Recording of previous events; Relapse; Reporting; Research; Risk; Route; Skin; Skin Temperature; Surface; Syringes; Temperature; Therapeutic; Thinness; Time; Tissues; Toxicology; Training; United States; Ventilatory Depression; Work; absorption; design; experience; hydrophilicity; in vivo; in vivo evaluation; innovation; loved ones; manufacturing scale-up; mass casualty; micropore; novel; opioid mortality; opioid overdose; overdose risk; patient population; prevent; prototype; receptor; subcutaneous; vehicular accident

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.

项目摘要/摘要 阿片类药物过量流行病正在大规模伤亡事件中杀死美国人 - 卡特里娜飓风杀害 1,577人，但仅在2018年在加利福尼亚，阿片类药物过量的死亡人数为5,348。合成，更多 芬太尼及其衍生物等有效的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通过将阿片类药物分子从 体内的受体，最终逆转呼吸道抑郁症。 NLX静脉注射（IV）， 肌肉内（IM），皮下（SC）或鼻内。不幸的是，所有市售剂型 有很大的缺点，使其面临院前环境的挑战。最值得注意的是，NLX患有 一个非常短的血浆半衰期，如果有大量阿片类药物，则会出现过量继电器的风险 等离子体。结果需要重复的NLX剂量（称为“救援”剂量），以防止缺氧， 所有交付途径都共享这场灾难，并且变得越来越普遍。额外的 挑战包括需要使用IV/IM/SC交付的针头/注射器，这在上下文中非常有风险 潜在混合的患者；鼻内递送不均匀有效，禁忌 鼻内损伤的背景通常会使用其他非法物质。在这项研究中，我们提出了 通过发展新型自动化，克服当前NLX剂型的缺点 带有微针的透皮贴片。长期目标是减少院前阿片类药物过量死亡 通过开发新型的透皮NLX剂型。目的是快速交付NLX 皮肤，旨在达到一致和治疗相关的药物浓度而无需营救 剂量。该提议的中心假设是NLX将通过表皮迅速，连续吸收 微孔和升高的皮肤温度与速率和程度之间将存在正相关 NLX渗透。该贴片将包括3层：1）溶解微针，2）透皮NLX凝胶和3）a 加热层。每一层都能实现特定的功能，并具有产生NLX皮肤渗透的综合效果 可以达到适合治疗阿片类药物过量的血浆水平。溶解NLX微针将 立即开始溶解NLX，同时也创建微孔以允许透皮NLX 从凝胶中递送。凝胶将通过微孔传递NLX，至少在贴片后2小时 应用。加热层将在暴露空气时迅速产生热量，升高皮肤温度和 从而增加NLX滥用的速度和程度。该补丁只需在一步之内应用。 在AIM 1中，我们将在体外优化每个贴片层以满足预定的里程碑以提供类似的交付 IM NLX交付的参数。在AIM 2中，斑块层将在药代动力学研究的体内进行测试 豚鼠。在资金期结束时，我们期望具有透皮NLX原型补丁 准备快速进入IND提交和初步人类研究。