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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要阿片类药物过量流行正在造成大规模伤亡事件的美国人死亡——卡特里娜飓风造成死亡 1,577 人，但 2018 年仅在加州就有 5,348 人因服用阿片类药物过量而死亡。芬太尼及其衍生物等强效阿片类药物进一步增加了死亡人数。 NLX 是一种阿片类药物拮抗剂，是阿片类药物过量的解毒剂，其作用是取代阿片类药物分子。 NLX 通过静脉注射（IV），最终逆转呼吸抑制。不幸的是，所有市售剂型均是肌内注射（IM）、皮下注射（SC）或鼻内注射。具有显着的缺点，使它们对院前环境具有挑战性。最值得注意的是，NLX 患有以下问题。血浆半衰期非常短，如果体内含有大量阿片类药物，则存在服药过量复发的风险这导致需要重复给予 NLX 剂量（称为“救援”剂量）以防止缺氧，所有运输途径都存在这一缺点，并且这一缺点正变得越来越普遍。挑战包括需要使用针头/注射器进行 IV/IM/SC 输送，这在当前情况下风险很大对于潜在好斗的患者，鼻内给药效果并不统一，并且在以下情况是禁忌的：在这项研究中，我们提出了使用其他非法物质时常见的鼻内损伤的情况。通过开发新型自加热克服当前 NLX 剂型的缺点带有微针的透皮贴剂的长期目标是减少院前阿片类药物过量死亡。通过开发新型透皮 NLX 剂型，目的是快速传递 NLX。皮肤，旨在达到一致且与治疗相关的药物浓度，无需救援该提案的中心假设是 NLX 将通过表皮快速、持续地吸收。微孔，并且皮肤温度升高与微孔的速率和程度之间存在正相关关系。 NLX 渗透贴片将包括 3 层：1）溶解微针，2）透皮 NLX 凝胶，3）每层都具有特定的功能，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。当 NLX 溶解时立即开始输送，同时还形成微孔以允许透皮 NLX 贴片后，凝胶将通过微孔输送 NLX 至少 2 小时。应用时，加热层暴露在空气中会迅速产生热量，从而增加皮肤温度和温度。提高 NLX 吸收的速度和程度，从而只需一步即可应用该贴片。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，从而提供类似的交付在目标 2 中，将在体内药代动力学研究中测试贴片层的参数。在资助期结束时，我们预计将有一个透皮 NLX 原型贴剂。准备好快速进入 IND 申请和初步人体研究。