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.

项目总结