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、 每月注射剂型和每年两次植入剂型这些处方的数量逐年增加。 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) 曲线显示初始爆发释放，随后趋于稳定。 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 长效注射和植入药物具有侵入性，需要 HCP 就诊。 为了解决这一未满足的需求，我们提出了一种“快速通道”的 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® 的商业成功提供了超过 1 个适用的案例研究。 数以百万计的女性选择 IVR 而不是传统方法：我们预计，这比长效植入物或贴片要多。 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 “pod”技术已在 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，我们开发了一种试点 BUP pod-IVR 并进行了测试。 我们在体外证实了 BUP 在绵羊体内具有生物利用度。 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 成功完成第一阶段的里程碑将是在绵羊身上进行安全性和药代动力学测试。 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 进一步证明该产品的安全性、PK和有效性。 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。