Longer-acting intravaginal formulation of buprenorphine

长效丁丙诺啡阴道内制剂

• 批准号: 10472754
• 负责人: Thomas J. Smith
• 金额: $ 84.53万
• 依托单位: AURITEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472754
• 关键词: Accreditation; Acquired Immunodeficiency Syndrome; Address; Adherence; Affect; Agonist; Americas; Animals; Antiviral Agents; Area; Biological Assay; Biological Availability; Buprenorphine; Case Study; Chemistry; Clinical; Clinical Management; Clinical Research; Clinical Trials; Colorado; Contraceptive Agents; Contraceptive methods; Contracts; Cytomegalovirus Retinitis; Development; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Environment; FDA approved; Formulation; Funding; Goals; HIV; Implant; In Vitro; Injectable; Investigational Drugs; Investigational New Drug Application; Knowledge; Lead; Licensing; Maintenance; Medication Management; Methods; Modality; Modeling; New Drug Approvals; Opiate Addiction; Opioid; Oral Contraceptives; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Polymer Chemistry; Privatization; Probability; Regulatory Affairs; Research; Research Personnel; Resources; Risk; Safety; Series; Sheep; Technology; Technology Transfer; Testing; Therapeutic; United States National Institutes of Health; Universities; Vagina; Vaginal Ring; Validation; Virginia; Visit; Woman; Work; addiction; analytical method; base; care outcomes; clinically relevant; experience; first-in-human; follow-up; genital herpes; improved; innovation; manufacturing process development; models and simulation; novel; novel therapeutics; opioid use disorder; pharmacokinetic model; phase 1 study; pre-clinical; pre-exposure prophylaxis; preclinical study; product development; programs; protocol development; response; safety testing; seal; sheep model; success; systemic toxicity; uptake

PROJECT SUMMARY 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.

项目摘要 该研究计划的广泛长期目标是赋予患有阿片类药物障碍的女性 （OUD）通过开发阿片类药物部分激动剂的长效静脉内环（IVR）公式 - 鲍多宁（BUP）。该建议是对RFA-DA-19-019的回应 “现有添加药物的长效配方”。 目前的基于BUP的药品用于治疗OUD的药品包括每日舌下， 每月注射式和两年一次的可植入公式。这些处方同比增加 表明改进的烟草药物具有改善患者保留率的巨大潜力，总体上 医疗保健结果。 尽管它们有用，但即时释放和长效bup公式都表现出优化 药代动力学（PK）曲线显示出初始爆发，然后是平稳性。每日公式 通常遭受依从性/合规性问题的困扰，并含有比要求的5-10倍的毒品加载，创建 转移潜力。长效注射和可植入药物是侵入性的，需要HCP访问 行政。为了满足这种未满足的需求，我们提出了一种“快速轨道”指定方法来开发 每月IVR使用我们既定的药物输送技术进行BUP。 避孕IVRNuvaring®的商业成功提供了适用的案例研究。超过1 百万妇女选择IVR而不是传统方法：长期效果或补丁多。我们期望 在很大一部分寻求OUD治疗的妇女中，将选择一个BUP环。 我们的团队具有制定IVR的经验，可以使用我们的 “ POD”技术。这项工作在HIV暴露前预防的领域获得了三项IND批准 （准备）和生殖器疱疹的治疗。在初步工作中，我们开发了一个飞行员bup pod-ivr并进行了测试 它在体外确认其公式可行性。我们确认BUP在绵羊中是有生物利用的 模型。 PK建模表明我们的POD-IVR可以基本上维持热等离子体水平 减少剂量和转移潜力。 第1阶段的具体目的是在广泛的释放目标上开发铅公式，并 在绵羊中进行安全性和PK测试。成功完成第一阶段的里程碑将是 从动物研究中证明安全性和临床相关的药物浓度。 在第2阶段，具体目标是：在化学，制造业和 控件（CMC）;临床前动物研究；和协议开发以允许里程碑：研究 FDA的新药（IND）津贴允许对BUP POD-IVR进行首次人工测试。 成功完成该项目后，我们将寻求资金进行一系列临床研究 进一步证明了安全性，PK和效率。该产品的开发将为女性提供小说， 私人和改进的治疗辅助功能，以优化成瘾，转移风险降低。