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.

项目概要 该研究计划的广泛、长期目标是赋予患有阿片类药物使用障碍的女性权力 (OUD) 通过开发阿片类部分激动剂的长效阴道环 (IVR) 制剂 -丁丙诺啡（BUP）。该提案是对 RFA-DA-19-019 的回应，该提案呼吁制定解决方案 “现有成瘾药物的长效制剂”。 目前用于治疗 OUD 的基于 BUP 的药品包括每日舌下含服、 每月注射一次和每年两次植入制剂。这些处方的逐年增加 表明改进的 BUP 药物对于提高患者保留率具有巨大潜力，并且总体而言 医疗保健成果。 尽管它们很有用，但速释和长效 BUP 制剂均表现出次优效果 药代动力学 (PK) 曲线显示最初的爆发释放，然后趋于稳定。每日配方 经常遭受依从性/依从性问题，并且载药量比所需多 5-10 倍，从而产生 分流潜力。长效注射剂和植入式药物具有侵入性，需要 HCP 就诊 行政。为了解决这一未满足的需求，我们提出了一种“快速通道”IND支持方法来开发 每月 IVR 使用我们成熟的药物输送技术输送 BUP。 避孕药 IVR Nuvaring® 的商业成功提供了一个适用的案例研究。超过 1 个 数以百万计的女性选择 IVR 而不是传统方法：比长效植入物或贴片更多。我们期望 很大一部分寻求 OUD 治疗的女性会选择 BUP 环。 我们的团队拥有配制 IVR 的经验，可以使用我们的 IVR 提供各种小分子和大分子 “吊舱”技术。这项工作已在 HIV 暴露前预防领域获得三项 IND 批准 （PrEP）和生殖器疱疹的治疗。在前期工作中，我们开发了一个试点BUP pod-IVR并进行了测试 进行体外实验以确认其制剂的可行性。我们证实 BUP 在绵羊体内具有阴道生物利用度 模型。 PK 模型表明，我们的 pod-IVR 可以将治疗血浆水平维持在相当高的水平。 减少剂量和转移潜力。 第一阶段的具体目标是开发具有广泛释放目标的先导制剂，并 对绵羊进行安全性和 PK 测试。第一阶段成功完成的里程碑将是 通过动物研究证明安全性和临床相关药物浓度。 第二阶段的具体目标是：在化学、制造和 控制（CMC）；临床前动物研究；和协议开发以实现里程碑：研究 FDA 授予新药 (IND) 许可，允许对 BUP pod-IVR 进行首次人体测试。 该项目成功完成后，我们将寻求资金进行一系列临床研究 进一步证明安全性、PK 和有效性。该产品的开发将为女性提供一种新颖、 治疗阿片成瘾的私人和改进的治疗辅助手段，可降低转移风险。