Ultra-long Acting Transcutaneously Refillable Islatravir Nanofluidic Implant for HIV Pre-Exposure

用于 HIV 暴露前的超长效经皮可再填充 Islatravir 纳米流体植入物

• 批准号: 10481727
• 负责人: Alessandro Grattoni
• 金额: $ 80.81万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481727
• 关键词: AIDS prevention; Address; Adherence; Anti-Retroviral Agents; Chronic; Clinical; Clinical Research; Complex; Developing Countries; Development; Devices; Diffuse; Diffusion; Dose; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Equipment; Excision; Fatigue; Formulation; Goals; HIV; HIV Infections; HIV antiretroviral; Heterogeneity; Human; Implant; Implantable Infusion Pumps; In Vitro; Individual; Injectable; Intravenous; Kinetics; Legal patent; Logistics; Manuals; Medical; Membrane; Modeling; Nickel; Operative Surgical Procedures; Oral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Physiological; Polymers; Prevention; Prevention strategy; Preventive; Pump; Recording of previous events; Regimen; Research; Route; Safety; Scanning Electron Microscopy; Silicon; Solid; Syringes; System; Technology; Testing; Therapeutic; Tissues; Vagina; Virus Diseases; base; biomaterial compatibility; clinical development; clinical translation; effectiveness evaluation; experience; global health; high risk; implantation; improved; innovation; minimally invasive; multidisciplinary; nanochannel; nanofluidic; nonhuman primate; penis; pill; pre-clinical; pre-exposure prophylaxis; preference; prevent; prophylactic; public health relevance; rectal; response; side effect; silicon carbide; simian human immunodeficiency virus; subcutaneous; transmission process; treatment duration; tripolyphosphate; viral transmission

Abstract Long-acting (LA) pre-exposure prophylactic (PrEP) strategies offer the promise of improving adherence to therapeutic regimen for maximal HIV preventive efficacy. Key attributes of zero-order release kinetics, long-term drug delivery, user-independent dosing, therapeutic discretion, safety for chronic use and retrievability are desirable criteria for successful widespread clinical PrEP implementation. To date, LA PrEP strategies do not sufficiently address the aforementioned criteria. Our goal is to address these limitations by developing an ultra- long acting islatravir (ISL) delivery implant with an unprecedented release duration of at least 2 years uninterrupted for durable and safe HIV prevention independent of user adherence. To achieve this goal, we propose the NanoDDI, a transcutaneously refillable subcutaneous nanofluidic drug delivery implant for sustained and constant ISL release. The NanoDDI comprises a newly patented nanofluidic membrane, and ports for rapid, minimally invasive transcutaneous drug refilling. Refilling is performed manually via a syringe without any complex pumps or equipment to extend implant use duration beyond 2 years. The nanofluidic membrane use nanochannels to control drug release through passive diffusion without pumping mechanisms, permitting discrete, long-term user-independent dosing. Unlike injectables or other LA polymeric strategies, NanoDDI avoids burst and decay release. Zero-order release kinetics is achieved independent of physiological conditions, regardless of interindividual heterogeneity. Importantly, the NanoDDI addresses user preferences for discretion and longer dose duration. Here we will test the hypothesis that constant and sustained ISL delivery from NanoDDI will achieve preventative drug levels for a 2-year duration and effectively prevent SHIV infection in non-human primates (NHP). This proposal outlines a comprehensive preclinical framework fundamental for developing NanoDDI as a HIV PrEP platform, leveraging the team’s experience in pre-clinical and clinical HIV PrEP, long-acting drug delivery, drug formulation, and antiretroviral pharmacology. We aim 1) to develop and optimize NanoDDI and ISL formulation for sustained and constant release; 2) to assess pharmacokinetics (PK), tolerability, and safety of NanoDDI-ISL for 2 years in NHP and evaluate effectiveness of transcutaneous drug refilling; and 3) to comprehensively evaluate PrEP efficacy of NanoDDI-ISL in NHPs using 4 routes of simian HIV transmission, namely rectal, penile, vaginal and intravenous. Our multidisciplinary team has a solid history of collaborative HIV PrEP studies with long-acting drug delivery implants and will receive Merck’s scientific and technical support and drug supply for this study. We will use a milestone-driven research approach to advance the NanoDDI-ISL technology towards the ultimate goal of clinical translation.

抽象的 长效 (LA) 暴露前预防 (PrEP) 策略有望提高患者的依从性 实现最大 HIV 预防功效的治疗方案 零级释放动力学的关键属性，长期。 药物输送、独立于使用者的剂量、治疗自由度、长期使用的安全性和可回收性 迄今为止，LA PrEP 策略还没有成功广泛实施临床 PrEP 的理想标准。 我们的目标是通过开发超强的解决方案来解决这些限制。 长效 islatravir (ISL) 递送植入物具有前所未有的至少 2 年的释放持续时间 不间断地持久、安全地预防艾滋病毒，与用户的依从性无关。为了实现这一目标，我们。 提出 NanoDDI，一种经皮可再填充的皮下纳米流体药物输送植入物，用于持续治疗 NanoDDI 包含新获得专利的纳米流体膜和快速、稳定的 ISL 释放端口。 微创经皮药物补充是通过注射器手动进行的，无需任何药物。 复杂的泵或设备可将植入物的使用期限延长至 2 年以上。 纳米通道通过被动扩散控制药物释放，无需泵机制，允许 与注射剂或其他 LA 聚合物策略不同，NanoDDI 是离散的、独立于用户的长期剂量。 避免爆发和衰变释放，实现独立于生理条件的零级释放动力学， 重要的是，无论个体之间的差异如何，NanoDDI 都会考虑用户的偏好。 和更长的剂量持续时间。 在这里，我们将测试以下假设：NanoDDI 持续且持续的 ISL 输送将实现预防性 药物水平持续 2 年并有效预防非人类灵长类动物 (NHP) 的 SHIV 感染。 提案概述了开发 NanoDDI 作为 HIV PrEP 的基础的全面临床前框架 平台，利用团队在临床前和临床 HIV PrEP、长效药物输送、药物 我们的目标是 1) 开发和优化 NanoDDI 和 ISL 制剂。 用于持续和恒定释放；2) 评估 NanoDDI-ISL 的药代动力学 (PK)、耐受性和安全性 在 NHP 工作 2 年并评估经皮药物补充的有效性；3) 全面评估 使用 4 种猿猴 HIV 传播途径（即直肠、阴茎、 阴道和静脉注射。 我们的多学科团队在 HIV PrEP 和长效药物输送方面的合作研究方面拥有丰富的历史 我们将使用植入物，并将获得默克公司的科学技术支持和药物供应。 里程碑驱动的研究方法，推动 NanoDDI-ISL 技术迈向临床最终目标 翻译。