Long acting biodegradable buprenorphine depots

项目摘要 丁丙诺啡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，并防止 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，其中一个 所有药物辅助治疗的主要问题是不依从性。为了解决这个问题，额外的更长时间的表演 必须开发生物可降解系统，以提供比目前可用的更长持续时间的BUP。以…为基础 该计划支持发现和开发预防和治疗阿片类药物使用障碍的药物 过量服药，朝着新剂量方案的可行产品快速发展，并易于为增加的 坚持应该是向前迈进的第一个、科学上合理和强有力的选择之一。 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 迄今为止在控释方面应用和研究最广泛的生物相容聚合物系统。因此， 与其他新型辅料或技术相比，FDA在监管和开发方面的障碍将更低。 这项研究和产品开发计划的目标是在健康人群中进行一项先导性的药物动力学临床试验 志愿者。我们的初步数据表明，可生物降解的棒剂可以通过释放曲线来制造。 与Probuphine®类似，并将在此项目期间进行优化。 该项目的具体目标是开发和优化一种可生物降解的乳棒配方，该配方可提供 ≥治疗动力学3个月。UG3阶段的里程碑是：(1)说明关键工艺参数 以及决定≥3个月体外释放动力学的材料属性；(Ii)≥3个月的成功展示 可生物降解单支避孕棒在犬体内的药代动力学研究(III) 通过与FDA的前IND会议的要求和途径；以及UH3阶段的要求和途径是：(Iv)成功转移 ≥3个月候选制剂的处方和制造通过体内研究证明 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 以及(Vii)≥在健康志愿者体内Cmin以上和Cmax以下的3个月药代动力学。 这项技术的创新是能够以可生物降解的形式控制BUP的释放动力学，同时 将初始爆炸降至最低；基于我们对PLGA微粒形成过程的机理理解， 使用具有特定分子性质的PLGA，并对制造条件进行严格控制。 利用挤压、可生物降解聚合物和压缩将使技术上的可转移性变得容易，因为 制药业已经大量使用流程，允许从学术界无缝过渡到 工业。此外，基于挤出的工艺已经被规模化，因为它是一个连续的工艺，并且基于PLGA 根据FDA目前批准的大约20种产品，这些配方此前已被证明是安全的 在市场上。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、随时可行的、必要的工具来帮助患者克服阿片类药物使用障碍。

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.