Novel formulation technology for the sustained release naloxone to improve outcomes in the management of opioid overdose

缓释纳洛酮的新型配方技术可改善阿片类药物过量的治疗结果

• 批准号: 10786306
• 负责人: Cesar Torres Luna
• 金额: $ 32万
• 依托单位: LYNTHERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10786306
• 关键词: Agitation; American; Animal Model; Behavioral; Bolus Infusion; Cell Survival; Centers for Disease Control and Prevention (U.S.); Central Nervous System; Cessation of life; Charge; Circulation; Competitive Binding; Contact Lenses; Data Reporting; Dose; Drug Delivery Systems; Effectiveness; Electrostatics; Emergency Care; Emergency treatment; Encapsulated; Esters; Exhibits; Eye diseases; Fentanyl; Formulation; Gel; Half-Life; Heart; Hydrogels; Implant; In Situ; In Vitro; Individual; Injectable; Kinetics; Legal patent; Lipids; Marketing; Mechanics; Metabolism; Modeling; Morphine; Musculoskeletal Pain; Naloxone; Nature; Nausea; Nose; Opiate Addiction; Opioid; Opioid Antagonist; Opioid Receptor; Outcome; Overdose; Oxygen; Oxymorphone; Pain management; Patients; Peripheral Nervous System; Persons; Pharmaceutical Preparations; Phase; Phase Transition; Physiological; Polymers; Property; Pulmonary Edema; Rattus; Risk; Seizures; Small Business Innovation Research Grant; Solid; Stimulus; Subcutaneous Injections; Surface; Sweating; Swelling; Symptoms; System; Technology; Temperature; Therapeutic; Toxic effect; United States; United States National Center for Health Statistics; Ventilatory Depression; Viscosity; Withdrawal Symptom; antinociception; aqueous; blood pressure elevation; copolymer; cost; craving; crystallinity; cytotoxicity; dosage; ethylene glycol; experience; fabrication; hydrophilicity; improved; improved outcome; in vivo; lipid nanoparticle; local drug delivery; mechanical properties; nanoparticle; novel; novel therapeutics; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; overdose death; prevent; protective effect; response; side effect; subcutaneous; synthetic opioid; therapeutic candidate

PROJECT SUMMARY Opioid overdose was responsible for less than 10,000 deaths in 1999 but increased to nearly 50,000 by 2019. Data reported by the Center for Diseases Control and Prevention's National Center for Health Statistics showed that the 12-month period leading up to April 2021 had more than 100,000 drug overdose deaths and over 74,000 opioid overdose deaths. Naloxone, derived from oxymorphone, decreases the effectiveness of opioids by competitively binding to µ-opioid receptors in the central nervous system. Even though naloxone has greatly helped to reduce the number of opioid overdose deaths, individuals with opioid use disorder often experience re-narcotization when treated with naloxone because of its relatively short half-life. Moreover, high or repeated doses of naloxone are needed to counteract its rapid metabolism with higher circulating naloxone levels, which can initiate precipitated opioid withdrawal symptoms in individuals with opioid addiction. This Phase I SBIR project will develop a cationic pH/temperature-sensitive hydrogel embedded with naloxone-encapsulated anionic solid lipid nanoparticles (SLNs) as an in situ gelling subcutaneous formulation for the long-lasting release of naloxone. The proposed hydrogel technology comprises a aqueous solution of a tri-block copolymer conjugated with poly(ethylene glycol) that once injected into the patient transitions to a gel under physiological conditions. Our approach will provide a double-encapsulation strategy for naloxone that would give an additional level of control over the spatial and temporal release while improving its stability. The nanoparticle-hydrogel composite will exploit the cationic nature of a stimuli-sensitive tri-block copolymer hydrogel system to achieve strong electrostatic interactions with naloxone loaded anionic SLNs, which would prolong the degradation and circulation of SLNs and therefore the activity of the loaded cargo. The first aim is the formulation and characterization of anionic naloxone-loaded SLNs dispersed in a cationic pH/temperature sensitive tri-block copolymer hydrogel system. This includes analyzing the properties of the hydrogel system such as the sol-gel phase diagram, viscosity, mechanical properties, swelling capacity, in vitro release kinetics, in vitro enzymatic degradation, and stability. The second aim evaluates the in vivo efficacy of the hydrogel system in a fentanyl- induced rat model of opioid overdose. A successful outcome will be a therapeutic candidate with sustained naloxone release which also can prevent fentanyl-induced respiratory depression and antinociception for up to 48 h following a single subcutaneous dose.

项目概要 1999 年，阿片类药物过量导致不到 10,000 人死亡，但到 2019 年，这一数字增加到近 50,000 人。 疾病预防控制中心国家卫生统计中心报告的数据显示 截至 2021 年 4 月的 12 个月期间，已有超过 100,000 人因药物过量死亡，超过 74,000 人 阿片类药物过量死亡。源自羟吗啡酮的纳洛酮会降低阿片类药物的有效性。 与中枢神经系统中的μ阿片受体竞争性结合，尽管纳洛酮具有很大的作用。 有助于减少阿片类药物过量死亡的人数，患有阿片类药物使用障碍的人经常经历 由于纳洛酮的半衰期相对较短，因此使用纳洛酮治疗时会再次麻醉。 需要一定剂量的纳洛酮来抵消其快速代谢与较高的循环纳洛酮水平，这 该 I 期 SBIR 可能会引发阿片类药物成瘾患者的突然阿片类药物戒断症状。 该项目将开发一种嵌入纳洛酮封装的阴离子的阳离子 pH/温度敏感水凝胶 固体纳米脂质颗粒（SLN）作为原位胶凝皮下制剂，可持久释放 所提出的水凝胶技术包含共轭三嵌段共聚物的水溶液。 聚乙二醇一旦注射到患者体内，在生理条件下就会转变为凝胶。 我们的方法将为纳洛酮提供双重封装策略，从而提供额外的水平 控制空间和时间释放，同时提高其稳定性。 将利用刺激敏感的三嵌段共聚物水凝胶系统的阳离子性质来实现强 与负载纳洛酮的阴离子 SLN 的静电相互作用，这会延长降解时间 SLN 的流通以及所装载货物的活动第一个目标是制定和实施。 分散在阳离子 pH/温度敏感三嵌段中的阴离子纳洛酮 SLN 的表征 这包括分析水凝胶系统（例如溶胶-凝胶）的特性。 相图、粘度、机械性能、溶胀能力、体外释放动力学、体外酶促 第二个目标是评估水凝胶系统在芬太尼中的体内功效。 诱导阿片类药物过量的大鼠模型将成为具有持续治疗作用的候选药物。 纳洛酮的释放还可以预防芬太尼引起的呼吸抑制和预期效果长达 单次皮下注射后 48 小时。