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

项目摘要/摘要 这项建议的目标是(1)确定注入植入物的最佳化学制剂 提供纳曲酮(NTX)，以最大限度地减少毒性，同时最大化疗效，(2)确定最佳 药物输送植入物的成分和孔隙率，以达到治疗血清中NTX的水平以及 (3)改进手术程序和器械，以促进安全和有效地部署 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：验证 NTX的两种剂型，脂质体包封剂和PLGA包封剂 在GLP/GCP下有体外稳定性和药代动力学证明的植入物。目标2：评估外科手术程序 以及用于可复制和安全植入的专门工具。目标3：优化NTX药物处方 体内植入设计。目标4：完成一项为期6至12个月的研究，以验证 申请研究新药/研究设备豁免所需的NTX植入物和 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关切和 美国国立卫生研究院作为研究小组，正在寻求一种根本性的解决方案和答案，以增进健康，延长寿命，减少 阿片类药物使用障碍患者的疾病和残疾(OUD)。 该项目的阶段将包括：工程、外科技术改进、药物配方、 生物分析评价：体内和体外，2个物种的外科植入，收集 药代动力学生物分析数据、毒理学/尸检研究和数据分析。具体的测试和 比较将包括NTX制剂(溶出组和体内1个月(啮齿动物))、球囊材料 在体内，(啮齿动物)，治疗(在体内6至12个月的啮齿动物和犬)，和对照(在体内的6至12个月 啮齿动物和犬类)和阿片类药物/芬太尼在犬类中的挑战。在体内试验成功结束后 在证实了有效性和安全性后，FDA将开始批准和临床试验。 在第一阶段的研究中，我们计划测试3种不同剂量的NI，以及一种安慰剂负载的植入物。 志愿者。NI的第二阶段临床试验将在有OUD的受试者中进行，以确定 NI的有效性、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 市售一个月缓释纳曲酮(XR-NTX)(Vivitrol，Alkermes) 按月给药，为期六个月。

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.