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

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。 疾病控制和预防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，有超过10万例药物过量死亡， 阿片类药物过量死亡来自羟吗啡酮的纳洛酮通过以下方式降低阿片类药物的有效性： 竞争性结合中枢神经系统中的μ-阿片受体。尽管纳洛酮在很大程度上 有助于减少阿片类药物过量死亡的人数，阿片类药物使用障碍的患者经常会经历 由于半衰期相对较短，使用纳洛酮治疗时会再次麻醉。此外，高或重复 需要一定剂量的纳洛酮来抵消其快速代谢和较高的循环纳洛酮水平， 可以引发阿片类药物成瘾个体的阿片类药物戒断症状。第一阶段SBIR 该项目将开发一种阳离子pH/温度敏感性水凝胶，其中嵌入纳洛酮包封的阴离子 固体脂质纳米粒（SLN）作为原位胶凝皮下制剂，用于长效释放 纳洛酮所提出的水凝胶技术包括三嵌段共聚物的水溶液， 其中聚（乙二醇）一旦注射到患者体内就在生理条件下转变成凝胶。 我们的方法将为纳洛酮提供一种双包封策略， 控制空间和时间释放，同时提高其稳定性。纳米颗粒-水凝胶复合物 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， 与纳洛酮负载的阴离子SLN的静电相互作用，这将延长降解， SLN的流通以及装载货物的活动。第一个目标是制定和 分散在阳离子pH/温度敏感三嵌段中的负载纳洛酮的阴离子SLN的表征 共聚物水凝胶体系。这包括分析水凝胶系统的性质，例如溶胶-凝胶 相图，粘度，力学性能，溶胀度，体外释放动力学，体外酶促 降解和稳定性。第二个目的是评价水凝胶系统在芬太尼-芬太尼复合物中的体内功效。 诱导阿片类药物过量大鼠模型。一个成功的结果将是一个治疗的候选人， 纳洛酮释放也可以防止芬太尼诱导的呼吸抑制和抗伤害作用， 单次皮下给药后48 h。

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.