I-Corps: Longer-acting intravaginal formulation of buprenorphine

项目总结 这项研究的长期目标是帮助患有阿片类药物使用障碍的女性。 通过开发阿片类部分激动剂的长效阴道内环(IVR)配方 丁丙诺啡(BUP)。快速通道提案是针对RFA-DA-19-019提交的，该提案要求 开发“现有成瘾药物的长效制剂”的解决方案。 目前治疗OUD的以BUP为基础的药物产品包括每日舌下， 每月注射，每两年植入一次。这些处方的同比增长 提示改进的BUP药物在改善患者保留率方面具有显著的潜力，总体而言 医疗保健结果。 尽管它们有用，但即刻释放和长效BUP制剂都显示出次优效果 药物动力学(PK)曲线显示最初的突释，然后进入平台期。日用配方 经常受到遵从性/遵从性问题的困扰，并且包含的药物负荷量是要求的5-10倍，从而 分流潜力。长效注射和植入性药物是侵入性的，需要去HCP就诊 行政管理。为了解决这一未得到满足的需求，我们提出了一种支持IND的快速通道方法，以开发 每月IVR递送BUP使用我们成熟的药物递送技术。 避孕药IVR Nuvering®的商业成功提供了一个适用的案例研究。多于1个 数百万妇女选择静脉注射受体，而不是传统的方法：比长效植入物或贴片更多。我们预计 将有相当大比例的女性选择乳房戒指来治疗OUD。 我们的团队有开发IVR的经验，可以使用我们的 “豆荚”技术。这项工作已经在艾滋病毒暴露前预防领域产生了三项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的BUP Pod-IVR并进行了测试 体外实验证实其制剂的可行性。我们证实了BUP在动物体内的阴道生物利用度 模特。PK模拟表明，我们的POD-IVR可以将治疗性血浆水平维持在基本上 减少了剂量和转移潜力。 第一阶段的具体目标是在广泛的释放目标范围内开发铅配方并 在动物身上进行安全和PK测试。成功完成第一阶段的里程碑将是 来自动物研究的安全性和临床相关药物浓度的演示。 在第二阶段，具体目标将是：开展所有必要的化学、制造和 对照(CMC)；临床前动物研究；以及方案开发，以实现里程碑：研究 FDA的新药(IND)津贴允许对BUP吊舱进行首次人体测试-IVR。 在这项计划成功完成后，我们会申请拨款进行一系列的临床研究，以 进一步证明安全性、PK和有效性。这款产品的开发将为女性提供一种新颖的， 私人和改进的治疗阿片成瘾的辅助治疗，降低了转移的风险。

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). The fast-track proposal was submitted 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 an animal 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 animals. 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.