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的重要疗法 过量。过去对BUP的使用既非常安全又有效。不幸的是，之一 所有药物辅助治疗的主要问题是不合规。为了解决这个问题，额外的行动更长 必须开发可生物降解系统以交付比当前可用的更长的bup。基于 该计划支持发现和开发用于预防和治疗阿片类药物使用障碍的药物和 过量，快速发展的新剂量方案的可行产品，并易于使用 依从性应该是前进的第一个，科学的声音和强大的选择之一。 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 迄今为止，在受控释放中，最广泛使用和研究的生物相容性聚合物系统。因此， 与其他新颖的赋形剂或技术相比，使用FDA的监管和发展障碍将“低”。 该研究和产品开发计划的目的是在健康中执行药代动力学临床试验 志愿者。我们的初步数据表明可以使用释放曲线制造可生物降解的杆配方 与ProbupHine®相似，并将在该项目的持续时间内进行优化。 该项目的具体目的是开发和优化提供可生物降解的bup杆配方 治疗动力学≥3个月。 UG3阶段的里程碑是：（i）说明关键过程参数 和材料属性决定了≥3个月的体外释放动力学； （ii）成功演示≥3个月 狗模型中的体内药代动力学来自单个可生物降解的bup杆（III）调节的确认 与FDA的预先开会会议的要求和途径；对于UH3阶段是：（iv）成功转移 ≥3个月候选公式A的公式和制造通过体内研究证明了 狗模型，（v）GLP局部公差研究完成（如果是FDA的要求），（vi）IND提交和清除 在健康志愿者中，FDA和（vii）在CMIN上方表现出≥3个月的药代动力学。 这项技术的创新是能够以可生物降解格式控制BUP释放动力学的能力，而 最小化初始爆发；根据我们对PLGA微粒形成过程的机械理解， 使用具有特定分子特性的PLGA，并对制造条件提供严格的控制。 利用扩展，可生物降解的聚合物和压缩将易于技术转移性 流程已经在制药行业已大量使用，可以从学术界无缝过渡到 行业。此外，基于扩展的过程已经缩放，因为它是一个连续的过程，而基于PLGA的过程 根据目前的大约20个FDA批准的产品，公式以前已被证明是安全的 在市场上。这项研究和产品开发的意义是该项目的最终结果 最终提供了一种新的，易于可行的基本工具，以帮助患者克服阿片类药物使用障碍。