A 3-month Release Naltrexone for Addiction Treatment

用于成瘾治疗的 3 个月缓释纳曲酮

• 批准号: 9620222
• 负责人: Timothy D Heath
• 金额: $ 20.26万
• 依托单位: PLUMB PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9620222
• 关键词: Adverse effects; Anesthesia procedures; Animals; Authorization documentation; Blood; Blood specimen; Buprenorphine; Businesses; Canis familiaris; Characteristics; Cities; Controlled Environment; Cryoelectron Microscopy; Dose; Drug Formulations; Drug Kinetics; Epidemic; Formulation; Health; Healthcare; Hour; Human; Implant; In Vitro; Injectable; Injections; Isoflurane; Laboratories; Lead; Lead Poisoning; Lipids; Liposomes; Maintenance; Maintenance Therapy; Methadone; Methods; Microspheres; Minor Surgical Procedures; Naltrexone; Opiate Addiction; Opioid; Opioid Antagonist; Opioid replacement therapy; Optics; Oral; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phospholipids; Physicians; Plasma; Population; Preparation; Procedures; Production; Productivity; Rattus; Reaction; Reproducibility; Rural; Russia; Schedule; Serum; Societies; Solvents; Sprague-Dawley Rats; Subcutaneous Injections; System; Technical Expertise; Technology; Testing; Time; Tissues; Tube; Variant; addiction; controlled release; cost; craving; efficacy study; experimental study; first-in-human; improved; in vitro Assay; in vivo; light scattering; medication compliance; methadone clinic/center; opioid misuse; particle; pill; rural area; scale up; social; subcutaneous; urban area; waiver; willingness

Opioid misuse is a world-wide problem, and it is increasing. The epidemic has shifted from a problem largely confined to urban areas to one that is both urban and rural. Maintenance therapy helps alleviate situa- tional cravings and makes addiction therapy more effective, but methadone clinics are largely confined to larger cities, buprenorphine must be prescribed by physicians with a specific waiver, and it may be difficult to find ‘waivered’ physicians in rural areas. Naltrexone is an opioid antagonist that has broad usage in the treat- ment of opioid addiction. Naltrexone may be prescribed by any physician; no special authorization is neces- sary. Naltrexone is only an opioid antagonist, and is not subject to diversion, unlike methadone and buprenor- phine, making naltrexone therapy more acceptable to more conservative populations. Naltrexone is the only approved maintenance therapy available to certain sensitive professions, and the only maintenance therapy available in certain parts of the world (like Russia). The original naltrexone formulation is a daily oral pill. Daily oral naltrexone is effective, but is subject to sig- nificant medication compliance issues. A monthly formulation of extended-release naltrexone, VivitrolÒ, is available, and improves medication compliance compared to daily oral pills, but it suffers from variations in re- lease rates over its duration as well as significant side effects that reduce patient willingness to continue treat- ment. Medication compliance (and efficacy) would be improved if the interval between injections could be in- creased to greater than 1 month and if the release rates were more stable over time. Our company, Plumb Pharmaceuticals, is developing an extended-release formulation of naltrexone and has assembled the technical expertise and the business team necessary to develop, test and eventually com- mercialize this formulation for addiction maintenance. Our proprietary Advanced Quantload technology can potentially extend the release period of naltrexone from the current 1 month to 18 weeks (4.5 months) in opi- oid-maintenance patients with a very stable release rate. An 18-week release period would be of special bene- fit to patients in rural areas. We will develop this ultra-extended release naltrexone formulation by completing of the following Aims: (1) Determine optimal encapsulation procedure, and characterize the product. Milestone: Establish efficient (>75%) loading of naltrexone (a ratio of at least 1.3 mg naltrexone per mg phospholipid) and characterize liposomes for size and type using light-scattering analysis and/or single particle optical sizing, and cryoelectron microscopy. (2) Determine the in vitro release characteristics of the AQL-Nal formulation from Aim 1. Milestone: the lead formulation will release 80% of its naltrexone in vitro at a uniform rate commensurate with an 18 week in vivo release period. (3) Conduct preliminary pharmacokinetics on the lead formulation in rats (n=36). Milestone: The lead formulation will demonstrate ≥ 1 ng/mL blood serum concentrations for 16-18 weeks with minimal systemic side effects/localized tissue reactions. In Phase II, we will further refine the prod- uct, perform GLP experiments in animals and first-in-human trials.

阿片类药物滥用是一个世界性的问题，而且还在增加。疫情已经从一个问题转变为 很大程度上局限于城市地区，既有城市也有农村。维持治疗有助于缓解这种情况- 性欲和成瘾治疗更有效，但美沙酮诊所在很大程度上限于 在较大的城市，丁丙诺啡必须由医生开具特定豁免的处方，而且可能很难 在农村地区找到被豁免的医生。纳曲酮是一种阿片类拮抗剂，在治疗糖尿病中有广泛的用途。 戒除阿片成瘾。纳曲酮可由任何内科医生开具；不需要特别授权- 萨里。纳曲酮只是一种阿片类拮抗剂，不会被转移，不像美沙酮和丁丙诺- Phine，使纳曲酮疗法更容易被更保守的人群接受。纳曲酮是唯一的 批准的维持疗法适用于某些敏感职业，也是唯一的维持疗法 在世界某些地区(如俄罗斯)可用。 最初的纳曲酮配方是一种每日口服药丸。每日口服纳曲酮是有效的，但需要接受信号检测。 严重的服药依从性问题。缓释纳曲酮的月度配方Vivitrol是 与每日口服药片相比，可用，并提高了服药依从性，但在复发率方面存在差异 租赁期内的租赁率以及降低患者继续治疗意愿的重大副作用- 门槛。如果两次注射之间的间隔可以在以下范围内，服药依从性(和疗效)将得到改善- 折痕超过1个月，如果释放速率随着时间的推移更稳定。 我们的公司Plumb PharmPharmticals正在开发纳曲酮和 已经组建了必要的技术专家和业务团队来开发、测试并最终实现COM- 美化这一配方以维持成瘾。我们专有的高级QuantLoad技术可以 可能将纳曲酮在OPI中的释放期从目前的1个月延长至18周(4.5个月)- 老年维持性患者具有非常稳定的释放率。18周的释放期将是特别有利的- 适合农村地区的患者。我们将通过完成以下工作来开发这种超缓释纳曲酮制剂 目的：(1)确定最佳包埋工艺，并对产品进行表征。里程碑： 建立有效的(&gt；75%)纳曲酮负荷(每毫克磷脂至少1.3毫克纳曲酮的比率)和 使用光散射分析和/或单颗粒光学测定来表征脂质体的大小和类型，以及 冷冻电子显微镜。(2)测定AQL-NAL制剂的体外释放度 1.里程碑：先导配方将以与之相称的统一速率在体外释放80%的纳曲酮 体内释放期为18周。(3)对铅制剂进行初步药代动力学研究 大鼠(n=36)。里程碑：铅配方将显示16-18年内≥的血清浓度为1 ng/ml 几周内全身副作用/局部组织反应最小。在第二阶段，我们会进一步完善产品- UCT，在动物身上进行GLP实验和第一次人体试验。