Injectable naltrexone 2-month depot formulations

注射用纳曲酮 2 个月储库制剂

• 批准号: 9796274
• 负责人: KINAM PARK
• 金额: $ 71.29万
• 依托单位: PURDUE UNIVERSITY
• 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/9796274
• 关键词: Adherence; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Consumption; Data; Development; Development Plans; Dose; Drug Delivery Systems; Drug Kinetics; Epidemic; Evaluation; Excipients; FDA approved; Fentanyl; Formulation; Glycolic-Lactic Acid Polyester; Goals; Illicit Drugs; In Vitro; Injectable; Injections; Internet; Kinetics; Laboratories; Methods; Molecular; Naltrexone; Needles; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid user; Oral; Outcome; Overdose; Pain; Paramedical Personnel; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Police officer; Price; Primates; Process; Property; Rattus; Regimen; Relapse; Research; Societies; Source; Street Drugs; Syringes; System; Technology; Testing; Time; Treatment Efficacy; Withdrawal Symptom; addiction; base; biocompatible polymer; carfentanil; combat; controlled release; design; drug addict; first responder; improved; in vivo; innovation; lead candidate; manufacturing scale-up; meetings; non-compliance; novel; opioid abuse; opioid epidemic; opioid overdose; opioid use disorder; overdose death; prescription drug abuse; prevent; product development; programs; research and development; small molecule; sound; tool; trend

Project Summary Naltrexone (NTX) has been proven as an important therapy in helping patients overcome opioid addition and in preventing overdose. Past usage of NTX has been shown to be both extremely safe and effective. Unfortunately, one of the major problems with NTX is noncompliance in therapy. To combat this issue, a system must be developed to deliver NTX for longer durations than currently available with a more patiently friendly format, specifically the duration of action, injection quantity/volume, and syringe needle size. With the basis of this program supporting the discovery and development of medications to prevent and treat opioid use disorders and overdose, rapid advancement towards a viable product for new dose regimens and ease of administration for increased adherence should be one of the first, scientifically sound, and robust choices moving forward. PLGA-based drug delivery systems have been used successfully in a number of small molecule products and are the most widely utilized and studied biocompatible polymer systems in controlled release. Therefore, the regulatory and development hurdles with the FDA will be `lower' than with other novel excipients or technologies. The goal of this research and product development plan is to submit a phase I application for a 2-month NTX formulation with favorable release kinetics and a patient-friendly format. Our preliminary data indicate two types of current, laboratory based systems can provide both a high drug loading and controllable release kinetics resulting of NTX for at least 2 months. The Specific Aim of this project is to optimize and bridge our laboratory scale 2-month injectable NTX delivery formulation to phase 1 clinical trials using 380 mg of NTX with a microparticle size of less than 100 µm for a less painful injection The Sub-Aims for the UG3 phase are: (i) Establish the design space for the two 2-month NTX (2M- NTX) formulations: Early Release (ER) and Delayed Release (DR); (ii) In vivo pharmacokinetic evaluations of 2M- NTX-ER and 2M-NTX-DR formulations; and for the UH3 phase (iii) GMP manufacturing scale-up of the lead candidate formulation; (iv) Lead candidate formulation nonclinical characterization; and (v) 505b2 IND submission for a phase I clinical trial. The innovation in this technology is the ability to control the NTX release kinetics while eliminating the initial burst; based on our mechanistic understanding of the PLGA microparticle formation process, using PLGAs with specific molecular properties, and providing tight control over the manufacturing conditions. This innovation has allowed us to design two specific types of formulations to aid in combating the opioid epidemic: (1) ER providing near zero-order release kinetics for two months and (2) DR providing an initial lag phase of 7-10 days, where minimal NTX release occurs, so it can be administered to patients who are still under the influence of opioids without precipitating withdrawal symptoms. PLGA-based microparticle formulations have previously been scaled and have been shown to be safe based on the approximate 20 FDA approved products currently on the market. The significance of this research and product development is the final outcome of this project will ultimately provide a new, readily viable, essential tool to help patients overcome opioid dependence.

项目概要 纳曲酮（NTX）已被证明是一种重要的治疗方法，可以帮助患者克服阿片类药物的添加问题，并在 防止服用过量。 NTX 的过去使用已被证明是极其安全和有效的。不幸的是，一 NTX 的主要问题之一是治疗不依从。为了解决这个问题，必须开发一个系统 以更耐心友好的格式提供比当前更长的 NTX 持续时间，特别是持续时间 作用、注射量/体积和注射器针头尺寸。在此计划的基础上支持这一发现 预防和治疗阿片类药物使用障碍和过量的药物的开发，快速推进 新剂量方案的可行产品和易于给药以提高依从性应该是首要任务之一， 科学合理、稳健的选择向前推进。 基于 PLGA 的药物递送系统已成功应用于许多小分子产品中，是 最广泛使用和研究的控释生物相容性聚合物系统。因此，监管和 FDA 的开发障碍将“低于”其他新型赋形剂或技术。此举的目标 研究和产品开发计划是提交为期 2 个月的 NTX 制剂的 I 期申请，并获得有利的 释放动力学和患者友好的形式。我们的初步数据表明当前有两种类型的基于实验室的 系统可以提供 NTX 的高载药量和可控释放动力学至少 2 个月。 该项目的具体目标是优化和桥接我们实验室规模的 2 个月注射 NTX 交付 使用 380 mg 微粒尺寸小于 100 µm 的 NTX 进行 1 期临床试验的配方，成本更低 UG3 阶段的子目标是： (i) 为两个 2 个月的 NTX（2M- NTX）制剂：早期释放（ER）和延迟释放（DR）； (ii) 2M-的体内药代动力学评估 NTX-ER和2M-NTX-DR配方；以及主要候选药物的 UH3 阶段 (iii) GMP 生产规模扩大 配方； (iv) 主要候选制剂的非临床表征； (v) 505b2 第一阶段 IND 提交 临床试验。该技术的创新之处在于能够控制 NTX 释放动力学，同时消除 初始爆发；基于我们对 PLGA 微粒形成过程的机械理解，使用 PLGA 特定的分子特性，并严格控制制造条件。这项创新有 使我们能够设计两种特定类型的配方来帮助对抗阿片类药物的流行：(1) ER 提供近 两个月的零级释放动力学，(2) DR 提供 7-10 天的初始滞后阶段，其中 NTX 最小 发生释放，因此可以将其施用给仍在阿片类药物影响下的患者，而不会发生沉淀 戒断症状。基于 PLGA 的微粒制剂之前已被规模化，并已被证明可以 根据目前市场上大约 20 种 FDA 批准的产品，该产品是安全的。本研究的意义 产品开发是该项目的最终成果，最终将提供一种新的、易于可行的、必不可少的工具 帮助患者克服阿片类药物依赖。