Combination Therapeutic for Chronic Opioid Use Disorder Relapse

慢性阿片类药物使用障碍复发的联合治疗

• 批准号: 10706844
• 负责人: TREVOR P. CASTOR
• 金额: $ 33.57万
• 依托单位: APHIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706844
• 关键词: Acids; Address; Adherence; Adult; Adverse effects; Aftercare; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Animals; Arousal; Behavior; Binding; Biological Availability; Buprenorphine; Cannabidiol; Cannabinoids; Cannabis sativa plant; Chronic; Clinical; Clinical Trials; Conduct Clinical Trials; Cue-induced relapse; Cues; Cyclic GMP; Dependence; Development; Dose; Drug Combinations; Economic Burden; Economics; Encapsulated; Epidemic; FDA approved; Female; Formulation; Frequencies; Friends; Funding; Future; Health Care Costs; Hemp; Heroin; Human; Hydrophobicity; In Vitro; Individual; Industry; Insulin; Intramuscular; Legal patent; Licensing; Marijuana; Medical; Methadone; Morphine; Motivation; Mus; Naltrexone; Nanosphere; Narcotics; Opiate Addiction; Opioid; Opioid Antagonist; Opioid abuser; Opioid agonist; Patients; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Polymers; Prevention; Proteins; Public Health; Regulatory Pathway; Relapse; Reporting; Research; Risk; Safety; Sister; Stomach; Stress; Technology; Therapeutic; Treatment Efficacy; United States; Wistar Rats; Withdrawal; Withdrawal Symptom; addiction; age group; biodegradable polymer; bryostatin; clinical development; craving; delta opioid receptor; experience; improved; in vivo; in vivo evaluation; lofexidine; male; manufacture; manufacturing scale-up; mu opioid receptors; nano; nanoencapsulated; nanoformulation; nanoparticle; nanopolymer; non-compliance; non-opioid analgesic; novel; opioid epidemic; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; pain symptom; pandemic disease; programs; relapse prevention; research and development; response; scale up; side effect; social; success; treatment adherence; treatment duration; uptake

PROJECT SUMMARY Few therapeutics are available for individuals trying to recover from opioid use disorder. Buprenorphine and methadone, opioid receptor agonists, are approved by the FDA to treat Opioid Use Disorder (OUD) but long- term efficacy and treatment adherence are sub-optimal. Extended-release naltrexone (Vivitrol®, Alkermes), a full µ-opioid receptor antagonist, was approved by the FDA in 2010 for the prevention of relapse to opioid dependence but initiation and adherence to treatment are low. There is an urgent need for improved treatments for chronic relapsing opioid use disorder that has serious public health consequences. For the treatment of chronic relapsing OUD, we propose to develop an extended-release combination of low- dose naltrexone and cannabidiol (CBD) by nanoencapsulating them in biodegradable polymer nanospheres using an environmental-friendly proprietary SuperFluids™ technology. CBD has been shown to inhibit cue- induced heroin seeking in animals, and subsequent human clinical trial studies have revealed its potential utility and safety. Animal studies have shown that low-dose naltrexone, when combined with CBD, is better than either of the two in isolation to improve motivation and alcohol consumption in mice. This combination is promising, considering that naltrexone primarily targets the μ opioid receptor, and CBD binds the μ and δ opioid receptors. Lowering the dose of naltrexone will be impactful since it will reduce the side effects of Vivitrol®, and improve safety and compliance. This novel formulation will significantly enhance the bioavailability and pharmacodynamics of the two therapeutics, reduce dose frequency, and improve addiction treatment adherence. In Phase I, we will develop nanoformulations of CBD and low-dose naltrexone/CBD in biodegradable polymer nanospheres, and assess the intramuscular administration of the nanoparticles to reduce OUD relapse compared to Vivitrol® in an animal model of OUD relapse. In Phase II, we will conduct a more extensive R&D program that includes scale-up of cGMP manufacturing, GLP in vitro and in vivo product characterization, and establish the regulatory pathway for clinical development. In Phase III, with strategic corporate partners and/or investors, we will conduct clinical trials of CBD/naltrexone PLGA nanoparticles in patients suffering from chronic relapsing opioid use disorder.

项目摘要 很少有治疗方法可用于试图从阿片类药物使用障碍中恢复的个人。丁丙诺啡和 美沙酮，阿片受体激动剂，被FDA批准用于治疗阿片类药物使用障碍（OUD），但长期以来， 长期疗效和治疗依从性是次优的。缓释纳洛酮（Vivitrol®，Alkermes），a 2010年，FDA批准了一种全μ阿片受体拮抗剂，用于预防阿片类药物复发 依赖性，但开始和坚持治疗的程度很低。迫切需要改进治疗方法 慢性复发性阿片类药物使用障碍，具有严重的公共卫生后果。 对于慢性复发性OUD的治疗，我们建议开发一种缓释组合， 通过将纳洛酮和大麻二酚（CBD）纳米包封在可生物降解的聚合物纳米球中来给药 采用环保的专有SuperFluids™技术。CBD已被证明可以抑制cue- 在动物中诱导海洛因寻求，随后的人类临床试验研究揭示了其潜在的效用 和安全性动物研究表明，低剂量纳洛酮与CBD结合使用时， 这两种药物单独用于改善小鼠的动力和酒精消耗。这种结合是有希望的， 考虑到纳洛酮主要靶向μ阿片受体，而CBD结合μ和δ阿片受体。 降低纳洛酮的剂量将是有影响的，因为它将减少Vivitrol®的副作用，并改善 安全性和合规性。这种新型制剂将显著提高生物利用度， 这两种治疗剂的药效学，减少剂量频率，并提高成瘾治疗依从性。 在第一阶段，我们将在可生物降解的聚合物中开发CBD和低剂量纳洛酮/CBD的纳米制剂。 纳米球，并评估肌内施用纳米颗粒以减少OUD复发 在OUD复发的动物模型中与Vivitrol®相比。在第二阶段，我们将进行更广泛的研发， 包括cGMP生产规模扩大、GLP体外和体内产品表征的计划，以及 建立临床开发的监管路径。在第三阶段，与战略企业伙伴和/或 投资者，我们将进行CBD/纳洛酮PLGA纳米颗粒在患有慢性 阿片类药物使用障碍复发