The broad, long-term goal of this research program is to empower women suffering from opioid use disorder (OUD) through the development of a long-acting intravaginal ring (IVR) formulation of the opioid partial agonist -buprenorphine (BUP). This proposal is in response to RFA-DA-19-019 which calls for solutions to develop Longer-acting formulations of existing addiction medications. The current armamentarium of BUP-based drug products for the treatment of OUD includes daily sublingual, monthly injectable, and bi-annual implantable formulations. The year-over-year increase in these prescriptions suggest that improved BUP medications hold significant potential for improving patient retention, and overall healthcare outcomes. Despite their usefulness, both immediate-release and long-acting BUP formulations demonstrate sub-optimal pharmacokinetic (PK) profiles displaying an initial burst release followed by plateauing. The daily formulations often suffer from adherence/compliance issues and contain 5-10X more drug loading than required, creating diversion potential. Long-acting injectable and implantable medications are invasive, and require HCP visits for administration. To address this unmet need, we propose a fast-track IND-enabling approach to develop a monthly IVR delivering BUP using our established drug delivery technology. The commercial success of the contraceptive IVR Nuvaring® provides an applicable case study. More than 1 million women choose IVRs over traditional methods: more than long-acting implants or patches. We expect that a BUP ring will be chosen by a significant percentage of women seeking treatment for OUD. Our team has experience formulating IVRs to deliver a wide variety of small and large molecules using our pod technology. This work has resulted in three IND approvals in the fields of HIV pre-exposure prophylaxis (PrEP) and the treatment of genital herpes. In preliminary work, we developed a pilot BUP pod-IVR and tested it in vitro to confirm its formulation feasibility. We confirmed that BUP is vaginally bioavailable in a sheep model. PK modeling indicates that our pod-IVR can maintain therapeutic plasma levels at a substantially reduced dose and diversion potential. The specific aims of Phase 1 are to develop lead formulations across a broad range of release targets and to perform safety and PK testing in sheep. The milestone for successful completion of Phase 1 will be the demonstration of safety and clinically relevant drug concentrations from the animal study. In Phase 2, the specific aims will be: to carry out all of the necessary work in chemistry, manufacturing and controls (CMC); pre-clinical animal studies; and protocol development to allow the milestone: Investigational New Drug (IND) allowance from the FDA allowing the first-in-human testing of a BUP pod-IVR. Following successful completion of this project, we will seek funding to carry out a series of clinical studies to further demonstrate safety, PK, and efficacy. The development of this product will provide women a novel, private and improved therapeutic adjunct in the treatment of opiate addiction with reduced risk for diversion.
Public Health Relevance Statement: PROJECT NARRATIVE The broad, long-term goal of this program is to develop a novel sustained release intravaginal ring (IVR) formulation for the maintenance treatment of women with opiate addiction. We have formulated a pilot IVR, which releases the FDA-approved drug substance buprenorphine in a sustained fashion for one month. Preliminary modeling indicates that this IVR can maintain clinically relevant plasma levels for a month at a substantially reduced dose compared to sublingual, buccal, or transdermal dosing. In this application, we propose to carry out all the formulation and pre-clinical work required to receive an approval of an Investigational New Drug (IND) from the FDA to begin testing of the IVR in women. The development of this product could provide women a novel, private and improved therapeutic adjunct for the treatment of opiate addiction, with reduced risk for diversion.
Project Terms: Accreditation; Acquired Immunodeficiency Syndrome; addiction; Address; Adherence; Affect; Agonist; Americas; analytical method; Animals; Antiviral Agents; Area; base; Bioavailable; Biological Assay; Biological Availability; Buprenorphine; care outcomes; Case Study; Chemistry; Clinical; Clinical Management; Clinical Research; Clinical Trials; clinically relevant; Colorado; Contraceptive Agents; Contraceptive methods; Contracts; Cytomegalovirus Retinitis; Development; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Environment; experience; FDA approved; first-in-human; follow-up; Formulation; Funding; genital herpes; Goals; HIV; Implant; improved; In Vitro; Injectable; innovation; Investigational Drugs; Investigational New Drug Application; Knowledge; Lead; Licensing; Maintenance; manufacturing process development; Medication Management; Methods; Modality; Modeling; models and simulation; New Drug Approvals; novel; novel therapeutics; Opiate Addiction; Opioid; opioid use disorder; Oral Contraceptives; Patients; Pharmaceutical Preparations; pharmacokinetic model; Pharmacologic Substance; Phase; phase 1 study; Plasma; Polymer Chemistry; pre-clinical; pre-exposure prophylaxis; preclinical study; Privatization; Probability; product development; programs; protocol development; Regulatory Affairs; Research; Research Personnel; Resources; response; Risk; Safety; safety testing; seal; Series; Sheep; success; systemic toxicity; Technology; Technology Transfer; Testing; Therapeutic; United States National Institutes of Health; Universities; uptake; Vagina; Vaginal Ring; Validation; Virginia; Visit; Woman; Work
