A 3-month Release Naltrexone for Addiction Treatment

阿片类药物滥用是一个世界性问题，而且正在增加。疫情已经从一个问题 主要局限于城市地区的一个城市和农村。维持治疗有助于缓解状况- 心理渴望，使成瘾治疗更有效，但美沙酮诊所主要限于 在较大的城市，丁丙诺啡必须由具有特定豁免权的医生处方，并且可能很难 在农村地区寻找“豁免”医生。纳洛酮是一种阿片类拮抗剂，广泛用于治疗- 阿片类药物成瘾。纳洛酮可由任何医生处方;不需要特别授权- 莎莉。纳洛酮只是一种阿片类拮抗剂，与美沙酮和丁丙诺不同，它不会被转移。 phine，使纳洛酮治疗更容易被更保守的人群接受。纳洛酮是唯一 批准的维持治疗提供给某些敏感的职业，唯一的维持治疗， 在世界上的某些地方（如俄罗斯）。 最初的纳洛酮配方是每日口服药丸。每日口服纳洛酮是有效的，但受到信号- 严重的药物依从性问题。缓释纳洛酮Vivitrolidone的每月制剂， 与每日口服药丸相比，它可以改善药物依从性，但它存在着重复用药的变化。 租赁率在其持续时间以及显着的副作用，降低病人愿意继续治疗- 我是说。如果注射之间的间隔可以在- 如果释放速率随时间推移更稳定，则增加至大于1个月。 我们的公司，Plumb Pharmaceuticals，正在开发一种纳洛酮的缓释制剂， 已经聚集了必要的技术专长和业务团队来开发，测试和最终COM- 使这种制剂商品化以维持成瘾。我们专有的Advanced Quantload技术可以 潜在地将纳洛酮的释放期从目前的1个月延长至18周（4.5个月）， 具有非常稳定的释放速率的维持性患者。18周的释放期将是特别的贝内- 适合农村地区的患者。我们将通过完成以下步骤来开发这种超缓释纳洛酮制剂： 目的：（1）确定最佳包封工艺，并对产品进行表征。里程碑： 建立纳洛酮的有效（>75%）载量（至少1.3 mg纳洛酮/mg磷脂的比例）， 使用光散射分析和/或单颗粒光学尺寸测定来表征脂质体的尺寸和类型，以及 冷冻电子显微镜(2)确定来自Aim的AQL-Nal制剂的体外释放特性 1.里程碑：先导制剂将在体外以均匀的速率释放80%的纳洛酮， 具有18周的体内释放期。(3)对先导制剂进行初步药代动力学研究， 大鼠（n=36）。里程碑：先导制剂将证明16-18天的血清浓度≥ 1 ng/mL 全身副作用/局部组织反应最小。在第二阶段，我们将进一步完善产品， 在动物和首次人体试验中进行GLP实验。

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.