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

用于治疗阿片类药物使用障碍的长效生物可吸收纳曲酮皮下植入物

• 批准号: 9796231
• 负责人: Jeffrey Benner
• 金额: $ 308.4万
• 依托单位: DRUG DELIVERY COMPANY, LLC, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796231
• 关键词: Address; Animal Testing; Animals; Autopsy; Biocompatible Materials; Canis familiaris; Chemicals; Clinical Trials; Collection; Data; Data Analyses; Data Analytics; Development; Devices; Doctor of Philosophy; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Implants; Drug Kinetics; Encapsulated; Engineering; Evaluation; Excision; FDA approved; Fentanyl; Formulation; Gel; Glycolates; Goals; Good Clinical Practice; Health; Human; Implant; In Vitro; Injections; Internet; Interview; Investigational Drugs; Label; Life; Liposomes; Macular degeneration; Marketing; Microspheres; Naltrexone; Operative Surgical Procedures; Opioid; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebos; Porosity; Preparation; Probability; Process; Proteins; Radio-Opaque; Rattus; Recovery; Regulatory Pathway; Relapse; Research; Rodent; Safety; Serum; Techniques; Testing; Therapeutic; Toxic effect; Toxicology; United States; United States National Institutes of Health; Ventilatory Depression; Work; addiction; base; bevacizumab; biomaterial compatibility; design; direct application; disability; good laboratory practice; healthy volunteer; implant design; implantation; improved; in vivo; instrument; instrumentation; non-compliance; opioid epidemic; opioid injection; opioid use disorder; overdose death; phase 1 study; pre-clinical; pre-clinical research; preclinical development; preclinical safety; prescription opioid; prevent; problem drinker; relapse patients; safety net; safety study; safety testing; small molecule; subcutaneous

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.

项目概要/摘要 该提案的目标是 (1) 确定注射到植入物中的最佳化学制剂 递送纳曲酮 (NTX) 以最大限度地降低毒性，同时最大限度地提高疗效，(2) 确定最佳方案 药物输送植入物的成分和孔隙率，以达到 NTX 的治疗血清水平以及 (3) 精细化手术流程和器械，以利于安全有效地部署 植入物。为了解决这些问题，研究团队将执行以下具体目标： 目标 1：验证 NTX 的两种配方，脂质体封装和 PLGA 封装，用于从 植入物具有 GLP/GCP 下的体外稳定性和药代动力学证明。目标 2：评估手术过程 以及用于可复制和安全植入的专用仪器。目标3：优化NTX药物配方 和体内植入物设计。目标 4：完成一项为期六至十二个月的研究，以验证该药物的安全性和有效性 研究性新药/研究性器械豁免申请所需的 NTX 植入物以及 临床试验。 由于阿片类药物危机持续存在，拟议的研究直接适用于国家的健康问题和 美国国立卫生研究院（NIH）作为研究团队寻求根本性的解决方案和答案，以增强健康、延长寿命和减少 患有阿片类药物使用障碍 (OUD) 的人的疾病和残疾。 该项目的阶段将包括：工程、手术技术改进、药物配方、 生物分析评估 - 体内和体外，手术植入 2 个物种，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。具体测试和 比较将包括 NTX 配方（溶出组和 1 个月体内（啮齿动物））、球囊材料 体内（啮齿动物）、治疗（6至12个月体内啮齿动物和犬）和对照（6至12个月体内） 啮齿类动物和犬类）以及犬科动物的阿片类药物/芬太尼挑战。体内试验成功结束后 随着疗效和安全性得到证实，FDA 批准和临床试验将开始。 在第一阶段研究中，我们计划在健康人群中测试 3 种不同剂量的 NI 以及安慰剂植入物。 志愿者。 NI 的 2 期临床试验将在 OUD 受试者中进行，以确定 NI 的功效、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 市售一个月缓释纳曲酮 (XR-NTX)（Vivitrol，Alkermes）的功效 每月给予一次，持续六个月。