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依赖和 防止服药过量。过去使用NTX已被证明是非常安全和有效的。不幸的是，有一个 NTX的主要问题之一是治疗不依从。为了解决这个问题，必须开发一种系统来 以更耐心友好的格式提供比当前可用的更长持续时间的NTX，特别是持续时间 作用的大小、注射量/体积和针头大小。在这个项目的基础上支持这一发现 以及预防和治疗阿片使用障碍和过量用药的药物的开发，迅速向 新剂量方案的可行产品和增加依从性的给药简便性应该是第一批产品之一， 科学上合理的，稳健的选择向前迈进。 基于PLGA的药物释放系统已经成功地应用于许多小分子产品中，并且是 最广泛地使用和研究生物相容的聚合物系统的控制释放。因此，监管机构和 FDA的开发障碍将比其他新型辅料或技术“更低”。这样做的目的是 研究和产品开发计划是提交为期2个月的NTX配方的第一阶段申请， 释放动力学和患者友好的形式。我们的初步数据显示了两种类型的电流，基于实验室 系统可以提供高载药量和可控释放动力学，导致NTX至少持续2个月。 这个项目的具体目标是优化和连接我们实验室规模的2个月注射NTX递送 配方到第一阶段临床试验使用380毫克的NTX，其微粒尺寸小于100微米，用于 疼痛注射UG3阶段的次要目标是：(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)体内药代动力学评价 NTX-ER和2M-NTX-DR配方；以及UH3阶段(三)主要候选者扩大GMP生产 配方；(4)主要候选配方的非临床特征；和(V)505b2 IND提交的第一阶段 临床试验。这项技术的创新是能够控制NTX的释放动力学，同时消除 最初的爆炸；基于我们对PLGA微粒形成过程的机理理解，使用PLGA和 特定的分子特性，并提供对制造条件的严格控制。这项创新已经 使我们能够设计两种特定类型的配方来帮助抗击阿片类药物的流行：(1)ER提供近 两个月的零级释放动力学和(2)DR提供7-10天的初始滞后阶段，其中NTX最小 发生释放，所以它可以用在仍然处于阿片类药物影响下的患者身上，而不会沉淀 戒断症状。基于PLGA的微粒子制剂以前已经过规模，并已被证明 基于目前市场上FDA批准的大约20种产品，确保安全。这项研究的意义 而产品开发是这个项目的最终成果，最终将提供一个新的、随时可行的、必不可少的工具 帮助患者克服阿片类药物依赖。