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

项目总结 阿片类药物过量在1999年导致不到10,000人死亡，但到2019年增加到近50,000人。 疾病控制和预防中心国家卫生统计中心报告的数据显示 在2021年4月之前的12个月里，有超过10万人死于药物过量，超过7.4万人死亡 阿片类药物过量死亡。纳洛酮源于羟吗啡酮，通过以下方式降低阿片类药物的有效性 与中枢神经系统中的阿片受体竞争性结合。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患者经常经历 由于纳洛酮的半衰期相对较短，因此在用纳洛酮治疗时会产生再麻醉作用。此外，高或重复的 需要剂量的纳洛酮来抵消其快速新陈代谢与更高的循环纳洛酮水平，这是 会在阿片成瘾患者中引发催促的阿片类药物戒断症状。此第一阶段SBIR 该项目将开发一种嵌入纳洛酮的阳离子pH/温度敏感水凝胶 固体脂质纳米粒(SLNS)作为一种原位凝胶皮下制剂的长效释放 纳洛酮。建议的水凝胶技术由三嵌段共聚物的水溶液组成。 一旦注入患者体内的聚乙二醇会在生理条件下转变为凝胶。 我们的方法将为纳洛酮提供双胶囊策略，这将使 在提高稳定性的同时，控制空间和时间的释放。纳米粒子-水凝胶复合材料 将利用一种对刺激敏感的三嵌段共聚物水凝胶体系的阳离子性质来实现 与纳洛酮负载的阴离子SLN的静电相互作用，将延长降解和 SLN的流通，从而影响装载货物的活动。第一个目标是制定和 阴离子纳洛酮SLN在阳离子pH/温度敏感三嵌段中的分散特性 共聚水凝胶体系。这包括分析诸如溶胶-凝胶之类的水凝胶体系的性质 相图、粘度、力学性能、溶胀量、体外释放动力学、体外酶促 退化和稳定。第二个目的是评价水凝胶系统在芬太尼中的体内疗效。 诱导大鼠阿片类药物过量模型。一个成功的结果将是一个持续的治疗候选 纳洛酮释放，也可以防止芬太尼引起的呼吸抑制和抗伤害作用 单次皮下注射后48小时。

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.