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.

Narrative The trends in opioid drug abuse and overdose deaths has continued relatively unabated. Buprenorphine has shown great promise in assisting people recovering from opioid dependence, but current treatment induction, retention, and regimens remain problematic for many. The goal of this project is to optimize and advance into clinical trials an injectable ≥3-month buprenorphine compressed single-rod formulation.