Injectable naltrexone 2-month depot formulations

注射用纳曲酮 2 个月储库制剂

• 批准号: 9897469
• 负责人: KINAM PARK
• 金额: $ 214.82万
• 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 2022-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897469
• 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; 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; opioid user; 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.

项目摘要 纳洛酮（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， 防止药物过量过去使用NTX已被证明是非常安全和有效的。不幸的是， NTX的主要问题是治疗中的不依从性。为了解决这个问题，必须建立一个系统， 以更耐心友好的格式，特别是持续时间，提供比目前更长的NTX持续时间 作用、注射量/体积和注射器针头尺寸。在这个项目的基础上， 以及预防和治疗阿片类药物使用障碍和过量的药物开发， 适用于新剂量方案和易于给药以提高依从性的可行产品应该是首要的产品之一， 科学合理的，稳健的选择向前发展。 基于PLGA的药物递送系统已成功地用于许多小分子产品中，并且是最好的药物递送系统。 在控制释放中最广泛使用和研究的生物相容性聚合物系统。因此，监管和 FDA的开发障碍将比其他新型赋形剂或技术“更低”。这个目标 研究和产品开发计划是提交一个为期2个月的NTX制剂的第一阶段申请， 释放动力学和患者友好的形式。我们的初步数据表明，两种类型的电流，实验室为基础的 系统可以提供高药物负载和NTX至少2个月的可控释放动力学。 该项目的具体目的是优化和桥接我们的实验室规模的2个月注射NTX输送 使用微粒尺寸小于100 µm的380 mg NTX进行1期临床试验， UG 3阶段的子目标是：（i）为两个为期2个月的NTX（2 M-1）建立设计空间。 NTX）制剂：早期释放（ER）和延迟释放（DR）;（ii）2 M-NTX的体内药代动力学评价 NTX-ER和2 M-NTX-DR制剂;以及UH 3阶段（iii）主要候选药物的GMP生产规模扩大 制剂;（iv）主要候选制剂非临床表征;和（v）I期505 b2 IND提交 临床试验该技术的创新在于能够控制NTX释放动力学，同时消除了 初始突释;基于我们对PLGA微粒形成过程的机械理解，使用PLGA与 特定的分子性质，并提供对制造条件的严格控制。这一创新 使我们能够设计两种特定类型的制剂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和（2）DR提供7-10天的初始滞后期，其中最小的NTX 释放发生，所以它可以给药给仍然在阿片类药物影响下的患者，而不会引起 戒断症状基于PLGA的微粒制剂先前已被规模化，并已显示出 根据目前市场上大约20种FDA批准的产品，本研究的意义 产品开发是这个项目的最终成果，最终将提供一个新的、可行的、必不可少的工具， 帮助患者克服阿片类药物依赖。