Prevention of renarcotization from synthetic opioids

预防合成阿片类药物的再麻醉

• 批准号: 9912548
• 负责人: Saadyah Averick
• 金额: $ 21.8万
• 依托单位: CONSEGNA PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912548
• 关键词: Acute; Address; Adipose tissue; American; Animal Model; Antidotes; Area; Behavior; Blood Circulation; Canis familiaris; Cessation of life; Chemicals; Chemistry; Clinical; Clinical Trials; Computer Simulation; Computer software; Coupled; Data; Dose; Drug Delivery Systems; Drug Kinetics; Emergency treatment; Ensure; Evaluation; Exhibits; FDA approved; Fentanyl; Formulation; Future; Generations; Goals; Government; Half-Life; Health; Heroin; Hospitals; Hour; Human; Hydrophobicity; In Vitro; Inhalation; Injectable; Institutes; Intellectual Property; Intravenous; Knowledge; Law Enforcement; Lead; Legal patent; Life; Manufacturer Name; Maps; Medical; Metabolic; Microencapsulations; Modeling; Monitor; Morphology; Naloxone; Names; Neurosciences; Opioid; Opioid Antagonist; Opioid agonist; Outcome; Overdose; Patient Noncompliance; Patients; Performance; Pharmaceutical Preparations; Phase; Plasma; Positioning Attribute; Prevention; Production; Property; Public Health; Recording of previous events; Regulatory Pathway; Reproducibility; Research; Research Institute; Residual state; Risk; Route; Sales; Sampling; Schedule; Secure; Small Business Technology Transfer Research; Technology; Testing; Therapeutic; Time; Tissues; Work; analog; animal facility; behavior in vitro; combat; commercialization; design; first responder; hydrophilicity; in vivo; innovation; medical specialties; mu opioid receptors; nanoparticle; nanopolymer; novel; off-patent; opioid epidemic; opioid mortality; opioid overdose; overdose death; particle; pre-clinical; preclinical trial; prevent; public health emergency; simulation; synthetic opioid; uptake

PROJECT SUMMARY/ABSTRACT In October 2017, the U.S. Government declared the current opioid epidemic the worst drug crisis in American history. Synthetically derived opioids such as fentanyl and fentanyl-derivatives have been at the forefront of this public health emergency, exhibiting the highest year-to-year contribution to overdose deaths. While the mu opioid receptor (MOR) antagonist naloxone has proven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half-life ~ 1hr.) and has been found to be less effective against newer, long acting opioids including fentanyl (half-life ~7-10 hrs.). This leads to a highly lethal and increasingly prevalent phenomenon known as “renarcotization”, wherein an overdose patient revived with naloxone can re-enter an overdose state from residual fentanyl in the body. To counter renarcotization, naloxone must be given repeatedly and at significantly higher doses than fentanyl. This approach may be achievable in a hospital; however, renarcotization is often not recognized outside a medical setting and can lead to death. Thus, there is a critical need to develop a long acting MOR antagonist formulation that can address renarcotization by providing the multi-hour protection. The goal of this Phase I STTR project is to reformulate naloxone using FDA approved microencapsulation technology into a long acting injectable (LAI) that can provide 12-24 hrs. of sustained antagonist activity in vivo. Other attempts to address this issue by chemically modifying naloxone are likely to suffer significant regulatory and technical risk. Consegna’s innovation is to employ its proprietary Computational Drug Delivery™ software, called ADSR™, to perform in silico formulation optimization as well as to predict its in vitro dissolution and in vivo pharmacokinetic behavior. Approval can be sought thru the 505(b)(2) accelerated regulatory pathway to gain near-term entry into the market since the naloxone molecule is not modified and efficacy is not at risk. This new long acting naloxone formulation, named CP216, will utilize an innovative design to address both primary and secondary overdose (renarcotization) situations thru a combination of free form naloxone for immediate effect and microencapsulated naloxone for sustained protection. Our hypothesis is that sustained release of naloxone from microparticles, coupled with an immediate release of free naloxone, can provide the therapeutics levels needed to reverse the overdose and prevent renarcotization. To test this hypothesis, 1) design an appropriate microparticle formulation and assess the formulation’s payload and release behavior in vitro, 2) evaluate the pharmacokinetics in an animal model, and 3) complete a Quality-by-Design assessment for a Chemistry, Manufacturing, and Controls package. Consegna believes this project has a significant potential to lead to the first safe and effective product to address renarcotization, and will lead to a positive impact on public health.

项目总结/摘要 2017年10月，美国政府宣布目前的阿片类药物流行病是美国最严重的毒品危机。 历史合成衍生的阿片类药物，如芬太尼和芬太尼衍生物，一直处于研究的最前沿。 这一公共卫生紧急情况，表现出最高的年度贡献过量死亡。而 μ阿片样物质受体（莫尔）拮抗剂纳洛酮已被证明作为阿片样物质过量解毒剂是无价的， 纳洛酮的作用持续时间非常短（半衰期约为1小时）。并且已经发现其效果较低 对抗包括芬太尼在内的新型长效阿片类药物（半衰期约为7-10小时）。这导致了一种高度致命的， 越来越普遍的现象被称为“再麻醉”，其中过量的病人复活， 纳洛酮可以从体内残留的芬太尼重新进入过量状态。 为了对抗再麻醉，纳洛酮必须反复使用，剂量明显高于芬太尼。 这种方法在医院可能是可行的;然而，在非急诊室， 医疗环境，并可能导致死亡。因此，迫切需要开发长效莫尔拮抗剂 可以通过提供多小时保护来解决再麻醉化的制剂。 该I期STTR项目的目标是使用FDA批准的微胶囊重新配制纳洛酮 技术转化为长效注射剂（LAI），可提供12-24小时。持续的拮抗剂活性。 其他通过化学修饰纳洛酮来解决这一问题的尝试可能会受到重大监管 技术风险。Consegna的创新是采用其专有的计算药物输送™软件， 称为ADSR™，以进行计算机模拟处方优化以及预测其体外溶出度和在 体内药代动力学行为。可通过505（B）（2）加速监管途径寻求批准， 获得短期进入市场，因为纳洛酮分子未被修饰，疗效没有风险。 这种新的长效纳洛酮制剂，命名为CP 216，将利用创新的设计，以解决这两个问题 原发性和继发性药物过量（再麻醉）情况，通过游离形式纳洛酮的组合， 即时效应和微囊纳洛酮持续保护。 我们的假设是，纳洛酮从微粒中的持续释放，加上立即释放的 游离纳洛酮可以提供逆转过量和防止再神经化所需的治疗水平。 为了检验该假设，1）设计适当的微粒制剂并评估制剂的 有效载荷和体外释放行为，2）评估动物模型中的药代动力学，和3）完成 化学、生产和控制包的设计质量评估。孔塞尼亚认为， 该项目有很大的潜力产生第一个安全有效的产品来解决再麻醉化问题， 将对公众健康产生积极影响。