Microneedle Delivery of Zanamivir for Treatment of Influenza

扎那米韦微针治疗流感

• 批准号: 10132966
• 负责人: Elke Lipka
• 金额: $ 95.22万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132966
• 关键词: Acute; Adamantane; Address; Animals; Antiviral Agents; Blood Circulation; Categories; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical Virology; Communicable Diseases; Communities; Data; Deglutition; Development; Development Plans; Disease; Dose; Drug Kinetics; Elderly; Ensure; Epidemic; Family suidae; Feedback; Ferrets; Fiber; Formulation; Horns; Human; Infection; Influenza; Inhalation; Investigational Drugs; Investigational New Drug Application; Lung; Medical; Methods; Miniature Swine; Modeling; National Institute of Allergy and Infectious Disease; Needles; Neuraminidase inhibitor; Oral; Oseltamivir; Painless; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Physicians; Population; Powder dose form; Puncture procedure; Regimen; Research; Resistance; Respiratory System; Route; Skin; Syringes; System; Testing; Therapeutic; Time; Toxicology; Transdermal substance administration; Treatment Efficacy; Vaccination; Vaccines; Validation; Virus; Visit; Work; absorption; anti-influenza; biothreat; clinical development; economic impact; effective therapy; efficacy study; efficacy testing; flu; in vivo; influenza epidemic; influenza infection; influenza outbreak; influenza virus strain; influenzavirus; meetings; mortality; novel; pain patient; pandemic disease; pandemic influenza; patient population; pharmacodynamic model; phase III trial; pre-clinical; preclinical safety; preclinical study; prevent; product development; prototype; reduce symptoms; resistant strain; respiratory; scale up; seasonal influenza; side effect; simulation; skin barrier; skin irritation; transmission process; vaccine effectiveness; zanamivir

Abstract Yearly influenza epidemics strike millions of people, causing up to 500,000 deaths. Fatality caused by most seasonal influenza viruses is <0.03%, but with significant mortality in the young and the elderly populations. When a new pathogenic influenza strain enters the population, a pandemic could kill tens of millions of people with a negative economic impact estimated to be over 150 billion dollars. Influenza virus is a NIAID category C priority biothreat, characterized as an emerging agent that is readily available and disseminated. Due to the incomplete efficacy of the current vaccines, effective drug treatment is necessary. Presently, influenza treatment is only somewhat effective, and some influenza strains are resistant to the currently marketed therapeutics, adamantanes and the neuraminidase inhibitor Tamiflu®. However, while zanamivir (Relenza®) remains highly active against oseltamivir-resistant influenza strains, its therapeutic impact is severely limited by its route of administration, via oral inhalation, which renders it unsuitable for patients with a compromised respiratory system. Therefore, development of a novel delivery alternative for zanamivir as we propose here, is poised to address a significant unmet medical need. Application of a transdermal microneedle (MN) delivery strategy to the anti-viral, and particularly anti-influenza, market offers a number of solutions to large unmet medical needs, and represents an attractive market entry strategy. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches do not require swallowing, eliminating oral side effects. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid any absorption and first-pass barriers a drug might encounter with oral delivery. Finally, transdermal delivery avoids skin puncture by syringe needles, eliminating pain and patient visits to a physician. Transdermal delivery of ZAN is desirable during seasonal and pandemic influenza outbreak, as large numbers of patients can be treated and the spread of the disease can be controlled. The Phase II portion of this proposal will involve formulation optimization and scale-up of the ZAN MN formulation and subsequent pharmacokinetic testing in minipigs and efficacy testing in ferrets. Human dose projections will be derived from simulation-guided PK/PD modeling and a confirmatory study in the hollow fiber infection model (HFIM). IND-enabling dermatotoxicology studies will complete the preclinical data package. All preclinical studies as well as the Phase I clinical development plans will be presented to the FDA during a pre-IND meeting. The end result of this work will be a novel, transdermal delivery approach for zanamivir with demonstrated efficacy, PK and preclinical safety data ready to open an IND application. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.

抽象的 每年流感流行都会袭击数百万人，导致多达 50 万人死亡。死亡大部分由 季节性流感病毒<0.03%，但在年轻人和老年人群中死亡率很高。 当一种新的致病性流感毒株进入人群时，大流行可能会导致数千万人死亡 预计造成的负面经济影响超过 1500 亿美元。流感病毒属于 NIAID C 类 优先生物威胁，其特征是一种容易获得和传播的新兴媒介。由于 目前的疫苗疗效不完全，有效的药物治疗是必要的。目前，流感治疗 仅有些效果，并且某些流感病毒株对目前市售的疗法具有抗药性， 金刚烷类和神经氨酸酶抑制剂达菲®。然而，虽然扎那米韦 (Relenza®) 仍然高度 其对奥司他韦耐药的流感病毒株具有活性，但其治疗效果受到其传播途径的严重限制。 通过口腔吸入给药，这使得它不适合呼吸系统受损的患者 系统。因此，正如我们在此建议的那样，开发扎那米韦的新型给药替代方案有望 解决重大的未满足的医疗需求。 透皮微针（MN）递送策略在抗病毒、特别是抗流感药物中的应用 市场为大量未满足的医疗需求提供了许多解决方案，并且代表了一个有吸引力的市场进入 战略。透皮递送系统比其他递送系统提供了许多改进。补丁 不需要吞咽，消除口服副作用。药物可透过皮肤直接渗透 进入体循环并避免药物口服时可能遇到的任何吸收和首过障碍 送货。最后，透皮给药避免了注射器针头刺穿皮肤，从而消除了疼痛和患者就诊 给医生。在季节性和大流行性流感爆发期间，ZAN 的透皮给药是可取的，因为 可以治疗大量患者并控制疾病的传播。 该提案的第二阶段部分将涉及 ZAN MN 配方的配方优化和放大 以及随后的小型猪药代动力学测试和雪貂功效测试。人体剂量预测将 源自模拟引导的 PK/PD 建模和中空纤维感染模型的验证性研究 （HFIM）。支持 IND 的皮肤毒理学研究将完成临床前数据包。所有临床前 研究以及 I 期临床开发计划将在 IND 前会议期间提交给 FDA。 这项工作的最终结果将是扎那米韦的一种新颖的透皮给药方法，并已被证明 功效、PK 和临床前安全性数据已准备好打开 IND 申请。我们组建了一支专家团队 顾问和合作者，以确保本研究计划的成功完成。