A Long-Acting Bioabsorbable Naltrexone Subcutaneous Implant for Opioid Use Disorder

项目总结/摘要 本提案的目标是（1）确定注入植入物的最佳化学制剂， 递送纳洛酮（NTX）以使毒性最小化，同时使功效最大化，（2）确定最佳的 药物递送植入物的组成和孔隙率以实现NTX的治疗血清水平以及 (3)完善手术程序和工具，以促进安全有效地展开 植入物为了解决这些问题，研究小组将执行以下具体目标：目标1： NTX的两种制剂，脂质体包封和PLGA包封，用于从 根据GLP/GCP，植入物具有体外稳定性和药代动力学证明。目的2：评估外科手术 和专门的器械进行可复制和安全的植入。目的3：优化NTX药物处方 和体内植入物设计。目的4：完成一项为期6至12个月的研究，以验证 试验用新药/试验用器械豁免申请所需的NTX植入物， 临床试验 由于阿片类药物危机挥之不去，拟议的研究直接适用于国家的健康问题， 美国国立卫生研究院作为研究小组寻求一个根本的解决方案和答案，以增强健康，延长寿命， 阿片类药物使用障碍（OUD）患者的疾病和残疾。 该项目的阶段将包括：工程、手术技术改进、药物配制、 生物分析评价-包括：体内和体外，2个种属的手术植入， 药代动力学生物分析数据、毒理学/尸检研究和数据分析。特殊的试验和 比较将包括NTX制剂（溶出度组和1个月体内（啮齿动物））、球囊材料 体内、（啮齿动物）、治疗（啮齿动物和犬体内6 - 12个月）和对照（体内6 - 12个月 啮齿动物和犬）和犬中的阿片样物质/芬太尼攻击。在体内试验成功结束后， 随着疗效和安全性的证明，FDA将批准和临床试验开始。 在I期研究中，我们计划在健康受试者中测试3种不同剂量的NI沿着安慰剂负载的植入物。 志愿者NI的II期临床试验将在OUD受试者中进行，以确定 NI的疗效、安全性、耐受性和药代动力学。我们将评估两种剂量的NI，并将其与 市售的一个月延长释放纳洛酮（XR-NTX）（Vivitrol，Alkermes）的功效 每月一次，持续六个月。

Project Summary/Abstract The objectives for this proposal are (1) determining the optimal chemical preparation to inject into the implant for delivery of Naltrexone (NTX) to minimize toxicity while maximizing efficacy, (2) determine the optimal composition and porosity of the drug delivery implant to achieve the therapeutic serum levels of NTX as well as (3) refinement of the surgical procedure and instrumentation to facilitate the safe and effective deployment of the implant. To address these issues, the study team will execute the following specific aims: Aim 1: Validate two formulations of NTX, liposomal encapsulation and PLGA encapsulation, for sustained release from the implant with proof of in vitro stability and pharmacokinetics under GLP/GCP. Aim 2: Assess surgical procedure and specialized instruments for replicable and safe implantation. Aim 3: Optimize the NTX drug formulation and implant design in vivo. Aim 4: Complete a six to twelve-month study to verify the safety and efficacy of the NTX implant needed for an Investigational New Drug/Investigational Device Exemption Application and clinical trials. As the opioid crisis lingers, the proposed study has direct application to the health concerns of the nation and to the NIH as the study team seeks a fundamental solution and answer to enhance health, lengthen life, and reduce illness and disability for those suffering from an Opioid Use Disorder (OUD). The phases of the project will include: engineering, surgical technique refinement, pharmaceutical formulation, bioanalytical evaluation - both: in vivo and in vitro, surgical implantation in 2 species, collection of the pharmacokinetic bio-analytical data, toxicology/necropsy studies and analysis of the data. Specific tests and comparisons will include NTX formulation (dissolution groups and 1-month in vivo (rodent)), balloon material in vivo, (rodent), therapeutic (6 to 12 month in vivo rodent and canine), and control (6 to 12 month in vivo rodent and canine) and opioid/fentanyl challenge in canines. Upon successful conclusion of the in vivo trials with proven efficacy and safety, FDA approval and clinical trials will begin. In the phase I study, we plan on testing 3 different doses of NI along with a placebo loaded implant in healthy volunteers. The phase 2 clinical trial of the NI will be performed in subjects with OUD to determine the efficacy, safety, tolerability and pharmacokinetics of the NI. We will assess two doses of NI and compare this to the efficacy of a commercially available one month extended release naltrexone (XR-NTX) (Vivitrol, Alkermes) given monthly for six months.