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.

项目摘要 阿片类药物过量在1999年造成不到10,000人死亡，但到2019年增加到近50,000人。 疾病控制与预防中心国家健康统计中心报告的数据显示 截至2021年4月的12个月期间，有超过100,000次药物过量死亡，超过74,000 Opioid过量死亡。源自甲摩phone的纳洛酮降低了卵虫类药物的有效性 在中枢神经系统中，竞争性与阿片受体结合。即使纳洛酮有很大的 有助于减少阿片类药物过量死亡的数量，阿片类药物使用障碍的人经常经历 由于其半衰期相对较短，因此用纳洛酮处理后重新宣传。而且，高或重复 需要纳洛酮的剂量来抵消其快速代谢，纳洛酮水平较高，这 可以在阿片类药物成瘾的患者中引发沉淀的阿片类药物戒断症状。这个阶段我sbir 项目将开发阳离子pH/温度敏感的水凝胶，该水凝胶用纳洛酮封装的阴离子嵌入 固体脂质纳米颗粒（SLN）作为原位胶凝皮配方，用于长期释放 纳洛酮。提出的水凝胶技术包括三块共聚物共轭的水溶液 在生理条件下，曾经注射到患者向凝胶过渡到凝胶的聚乙二醇（乙二醇）。 我们的方法将为纳洛酮提供双重塑造策略 控制空间和临时释放，同时改善其稳定性。纳米颗粒 - 凝胶凝胶复合材料 将探索对刺激敏感的三块共聚物水凝胶系统的阳离子性质 与纳洛酮负载的阴离子SLN的静电相互作用，这将延长降解和 SLN的循环，因此是装载货物的活性。第一个目的是公式和 在阳离子pH/温度敏感的三块中分散的阴离子纳洛酮SLN的表征 共聚物水凝胶系统。这包括分析水凝胶系统的性能，例如溶胶 - 凝胶 相图，粘度，机械性能，肿胀能力，体外释放动力学，体外酶促 退化和稳定性。第二个目标评估了芬太尼 - 水凝胶系统的体内效率 诱导阿片类药物过量的大鼠模型。成功的结果将是持续的治疗候选人 纳洛酮释放也可以防止芬太尼诱导的呼吸抑郁症和抗伤害感受 单个皮下剂量后48小时。