Long acting biodegradable buprenorphine depots

长效可生物降解丁丙诺啡储库

• 批准号: 10757180
• 负责人: Andrew Otte
• 金额: $ 63.14万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757180
• 关键词: Academia; Acids; Adherence; Aftercare; Agonist; American; Behavior Therapy; Buprenorphine; COVID-19 pandemic; Characteristics; Clinic; Clinical; Clinical Research; Clinical Trials; Communities; Computing Methodologies; Counseling; Data; Development; Development Plans; Dimensions; Dose; Dropout; Drug Controls; Drug Delivery Systems; Drug Industry; Drug Kinetics; Drug Utilization; Dryness; Equilibrium; Event; Excipients; Excision; Family; Fiber; Formulation; Foundations; Goals; Government; Implant; Improve Access; In Vitro; Individual; Industry; Injectable; Kinetics; Length; Marketing; Methadone; Modality; Molecular; Naltrexone; Opiate Addiction; Opioid; Opioid Antagonist; Opioid replacement therapy; Outcome; Overdose; Pathway interactions; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Physicians; Polymers; Pre-Clinical Model; Process; Property; Regimen; Research; Research Project Grants; Rod; Rodent Model; Substance Use Disorder; System; Technology; Therapeutic; Toxic effect; United States Food and Drug Administration; Workplace; acute care; antagonist; base; biocompatible polymer; biodegradable polymer; buprenorphine treatment; candidate selection; canine model; combat; controlled release; design; drug release kinetics; expectation; experience; healthy volunteer; improved; in vitro Model; in vivo; innovation; kappa opioid receptors; manufacture; medication-assisted treatment; meetings; mu opioid receptors; non-compliance; novel; opioid abuse; opioid epidemic; opioid use disorder; overdose death; pandemic disease; particle; prevent; product development; programs; research and development; retention rate; small molecule; sound; substance use treatment; therapy duration; tool; treatment duration; trend

Project Summary Buprenorphine has been proven as an important therapy in helping patients overcome opioid addition and in preventing overdose. Past usage of BUP has been shown to be both extremely safe and effective. Unfortunately, one of the major problems with all medication assisted treatment is noncompliance. To combat this issue, additional longer acting biodegradable systems must be develop to deliver BUP for longer durations than currently available. 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 to date. 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 perform a pilot pharmacokinetic clinical trial in healthy volunteers. Our preliminary data indicates a biodegradable rod formulation can be fabricated with release profiles similar to that of Probuphine®, and will be optimized over the duration of this project. The Specific Aim of this project is to develop and optimize a biodegradable BUP rod formulation that provides therapeutic kinetics for ≥3 months. The Milestones for the UG3 phase are: (i) Illustrate the critical process parameters and material attributes that dictate the in vitro release kinetics of a ≥3-month; (ii) Successful demonstration of ≥3-month in vivo pharmacokinetics in the dog model from a single biodegradable BUP rod (iii) Confirmation of regulatory requirement and pathway through a preIND meeting with the FDA; and for the UH3 phase are: (iv) Successfully transfer the formulation and manufacturing of the ≥3-month candidate formulation a demonstrated through in vivo studies in the dog model, (v) Completion of GLP local tolerance study (if required by FDA), (vi) IND submission and clearance from the FDA, and (vii) Demonstrate ≥3-month pharmacokinetics above the Cmin and below the Cmax in healthy volunteers. The innovation in this technology is the ability to control the BUP release kinetics in a biodegradable format while minimizing 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. Utilizing extrusion, biodegradable polymer, and compression will enable readily technical transferability as these processes are already heavily utilized in the pharmaceutical industry, allowing for a seamless transition from academia to industry. Furthermore, extrusion-based processes are already scaled in that it is a continuous process, and PLGA-based formulations have previously 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 use disorder.

项目摘要 丁丙诺啡已被证明是帮助患者克服阿片类药物添加和预防 服药过量过去使用BUP已被证明是非常安全和有效的。不幸的是， 所有药物辅助治疗的主要问题是不依从。为了解决这个问题，额外的长效 必须开发生物可降解系统以比目前可获得的更长的持续时间递送BUP。根据 该计划支持药物的发现和开发，以预防和治疗阿片类药物使用障碍， 过量，快速发展为新剂量方案的可行产品，易于给药， 坚持应该是向前迈进的第一个、科学合理的和强有力的选择之一。 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。 迄今为止在控释中最广泛使用和研究的生物相容性聚合物系统。因此 FDA的监管和开发障碍将比其他新型赋形剂或技术“更低”。 本研究和产品开发计划的目标是在健康受试者中进行初步药代动力学临床试验。 志愿者我们的初步数据表明，可生物降解的棒配方可以制造释放曲线 类似于Probuphine®，并将在本项目期间进行优化。 该项目的具体目标是开发和优化可生物降解的BUP棒配方， 治疗动力学≥3个月。UG 3阶段的重要性为：（i）说明关键工艺参数 和决定体外释放动力学≥3个月的材料属性;（ii）成功证明≥3个月 （iii）来自单个可生物降解的BUP棒的狗模型中的体内药代动力学的确认 通过与FDA的preIND会议的要求和途径;对于UH 3阶段：（iv）成功转移 通过体内研究证明了≥3个月候选制剂A的配制和生产 犬模型，（v）完成GLP局部耐受性研究（如果FDA要求），（vi）IND提交和批准 FDA，和（vii）证明在健康志愿者中≥3个月的药代动力学高于Cmin且低于Cmax。 该技术的创新在于能够以可生物降解的形式控制BUP释放动力学， 使初始突释最小化;基于我们对PLGA微粒形成过程的机理理解， 使用具有特定分子特性的PLGA，并对生产条件进行严格控制。 利用挤出、可生物降解的聚合物和压缩将使得容易实现技术转移，因为这些 过程已经在制药行业大量使用，允许从学术界无缝过渡到 行业此外，基于挤出的方法已经成规模，因为它是连续的方法，并且基于PLGA的方法是连续的。 根据目前FDA批准的大约20种产品， 市场上本研究的意义和产品开发是本项目的最终成果 最终提供一种新的、可行的、基本的工具来帮助患者克服阿片类药物使用障碍。