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 这项研究计划的广泛，长期目标是增强患有阿片类药物使用障碍的妇女的权能。 (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）。本提案是对RFA-DA-19 - 019的回应，RFA-DA-19 - 019要求开发解决方案 “现有成瘾药物的长效制剂”。 目前用于治疗OUD的基于BUP的药物产品的方法包括每日舌下， 每月注射一次和一年两次的可植入制剂。这些处方的逐年增长 表明改进的BUP药物具有改善患者保留的显著潜力， 医疗结果。 尽管它们是有用的，但速释和长效BUP制剂都表现出次优的 药物代谢动力学（PK）曲线显示初始突释，然后是平台期。每日配方 通常存在依从性/顺应性问题，并且含有比所需多5 - 10倍的药物负载， 转移潜力。长效注射和植入药物是侵入性的，需要HCP访视， 局为了解决这一未得到满足的需求，我们提出了一个"快速通道"的自主研发方法， 使用我们已建立的药物递送技术每月IVR递送BUP。 IVR Nuvaring®避孕药的商业成功提供了一个适用的案例研究。超过1 百万妇女选择IVRs而不是传统方法：比长效植入物或贴片更多。我们预计 BUP环将被寻求治疗OUD的女性的显着比例所选择。 我们的团队具有制定IVR的经验，可以使用我们的 "豆荚"技术。这项工作已导致在艾滋病毒暴露前预防领域的三个IND批准 生殖器疱疹的治疗方法有哪些？在初步工作中，我们开发了一个试点BUP播客-IVR和测试 通过体外实验验证其配方的可行性。我们证实了BUP在绵羊阴道中具有生物利用度 模型PK模型表明，我们的pod-IVR可以将治疗血浆水平维持在 减少剂量和转移潜力。 第1阶段的具体目标是开发涵盖广泛释放目标的铅制剂， 在绵羊中进行安全性和PK试验。成功完成第一阶段的里程碑将是 动物研究的安全性和临床相关药物浓度证明。 在第二阶段，具体目标将是：在化学、制造和生产方面开展所有必要的工作， 对照（CMC）;临床前动物研究;以及方案制定，以实现里程碑：研究 FDA的新药（IND）许可允许BUP pod-IVR的首次人体试验。 在这项计划成功完成后，我们会申请拨款进行一系列临床研究， 进一步证明安全性、PK和疗效。该产品的开发将为女性提供一种新颖， 在阿片类药物成瘾治疗中使用的私人和改进的治疗辅助剂，减少了转移的风险。