Project Summary/Abstract The objectives for this proposal are (1) determining the optimal chemical preparation to inject into the implant for delivery of Naltrexone (NTX) to minimize toxicity while maximizing efficacy, (2) determine the optimal composition and porosity of the drug delivery implant to achieve the therapeutic serum levels of NTX as well as (3) refinement of the surgical procedure and instrumentation to facilitate the safe and effective deployment of the implant. To address these issues, the study team will execute the following specific aims: Aim 1: Validate two formulations of NTX, liposomal encapsulation and PLGA encapsulation, for sustained release from the implant with proof of in vitro stability and pharmacokinetics under GLP/GCP. Aim 2: Assess surgical procedure and specialized instruments for replicable and safe implantation. Aim 3: Optimize the NTX drug formulation and implant design in vivo. Aim 4: Complete a six to twelve-month study to verify the safety and efficacy of the NTX implant needed for an Investigational New Drug/Investigational Device Exemption Application and clinical trials. As the opioid crisis lingers, the proposed study has direct application to the health concerns of the nation and to the NIH as the study team seeks a fundamental solution and answer to enhance health, lengthen life, and reduce illness and disability for those suffering from an Opioid Use Disorder (OUD). The phases of the project will include: engineering, surgical technique refinement, pharmaceutical formulation, bioanalytical evaluation - both: in vivo and in vitro, surgical implantation in 2 species, collection of the pharmacokinetic bio-analytical data, toxicology/necropsy studies and analysis of the data. Specific tests and comparisons will include NTX formulation (dissolution groups and 1-month in vivo (rodent)), balloon material in vivo, (rodent), therapeutic (6 to 12 month in vivo rodent and canine), and control (6 to 12 month in vivo rodent and canine) and opioid/fentanyl challenge in canines. Upon successful conclusion of the in vivo trials with proven efficacy and safety, FDA approval and clinical trials will begin. In the phase I study, we plan on testing 3 different doses of NI along with a placebo loaded implant in healthy volunteers. The phase 2 clinical trial of the NI will be performed in subjects with OUD to determine the efficacy, safety, tolerability and pharmacokinetics of the NI. We will assess two doses of NI and compare this to the efficacy of a commercially available one month extended release naltrexone (XR-NTX) (Vivitrol, Alkermes) given monthly for six months.

Project Narrative – “Relevance” The proposed research addresses the critical barrier of non-compliance with both oral NTX and XR-NTX that prevent these treatments from helping more patients with Opioid Use Disorder (OUD). A sustained release NTX implant that works for six to twelve months would likely improve compliance and prevent fatal respiratory depression and overdose deaths in addicts who relapse and inject opioids while in recovery, providing a “safety net” which will allow for mistakes in the recovery process without deadly consequences.