Injectable naltrexone 2-month depot formulations

注射用纳曲酮 2 个月储库制剂

• 批准号: 10531766
• 负责人: KINAM PARK
• 金额: $ 88.81万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531766
• 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; Oral; Outcome; Overdose; Pain; Paramedical Personnel; Patient-Focused Outcomes; Patients; Persons; 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; 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; opioid user; overdose death; prescription drug abuse; prevent; product development; programs; research and development; small molecule; sound; therapeutically effective; 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.

项目摘要 纳曲酮（NTX）已被证明是帮助患者克服阿片类药物的重要疗法 防止过量。过去对NTX的使用既是非常安全又有效的。不幸的是，一个 NTX的主要问题是治疗中的不合规。要解决这个问题，必须开发系统 与当前更耐心更友好的格式相比，交付NTX的持续时间更长，特别是持续时间 动作，注入数量/体积和注射针头尺寸。在支持发现的基础上 以及开发用于预防和治疗阿片类药物使用障碍和过量服用的药物，快速发展 新剂量方案的可行产品和依从性依从性的依从性应该是第一个的产品之一， 科学的声音，强大的选择向前发展。 基于PLGA的药物输送系统已成功地用于许多小分子产品中，是 在受控释放中，最广泛的利用和研究生物相容性聚合物系统。因此，监管和 与其他新颖的赋形剂或技术相比，使用FDA的开发障碍将是“低”。目标的目标 研究和产品开发计划是为2个月的NTX公式提交I期申请 释放动力学和患者友好的格式。我们的初步数据，指示两种类型的基于实验室的类型 系统可以提供高药物负荷和受控释放动力学，从而导致NTX至少2个月。 该项目的具体目的是优化和桥接我们的实验室规模2个月可注射的NTX交付 使用380毫克的NTX构成1阶段临床试验，微粒尺寸小于100 µm，较小 痛苦的注射UG3阶段的子AIM是：（i）为两个2个月的NTX建立设计空间（2m-- NTX）公式：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公式；对于UH3阶段（III）GMP制造量表的规模 公式; （iv）主要候选公式非临床表征； （v）I阶段I的505b2 IND提交 临床试验。该技术的创新是控制NTX释放动力学的能力，同时消除了 初始爆发；根据我们对PLGA微粒形成过程的机械理解，使用PLGA 特定的分子特性，并对制造条件提供严格的控制。这项创新有 允许我们设计两种特定类型的配方，以帮助梳理阿片类药物流行：（1）ER提供附近 零级释放动力学两个月，（2）DR提供7-10天的初始滞后阶段，其中最小NTX 发生释放，因此可以对仍处于阿片类药物影响的患者而不会沉淀 戒断症状。以前已经对基于PLGA的微粒公式进行了缩放，并已显示为 根据目前市场上的大约20个FDA批准的产品，请确保安全。这项研究的意义 产品开发是该项目的最终结果，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性。