Microneedle Delivery of Zanamivir for Treatment of Influenza

摘要 每年的流感疫情袭击数百万人，造成多达50万人死亡。由MOST引起的死亡 季节性流感病毒的感染率为0.03%，但在年轻人和老年人中具有显著的死亡率。 当一种新的致病性流感毒株进入人群时，一场大流行可能会导致数千万人死亡。 造成的负面经济影响估计超过1500亿美元。流感病毒是NIAID C类病毒 优先生物制剂，其特征是一种易于获得和传播的新兴制剂。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，流感的治疗 只有一定的效果，而且一些流感病毒株对目前市场上销售的治疗药物有抗药性， 金刚烷和神经氨酸酶抑制剂达菲®。然而，尽管扎那米韦(瑞乐沙®)仍然很高 对耐奥司他韦的流感病毒株有效，其治疗效果受到其途径的严重限制 口服给药，这使其不适合呼吸功能受损的患者 系统。因此，我们在这里提出的扎那米韦新型给药替代品的开发有望实现 解决未得到满足的重大医疗需求。 将经皮微针(MN)递送策略应用于抗病毒，特别是抗流感， Market为大量未得到满足的医疗需求提供了许多解决方案，并代表着一个有吸引力的市场进入 策略。与其他给药系统相比，透皮给药系统提供了许多改进。补片 不需要吞咽，消除口服副作用。通过皮肤的渗透使药物能够直接 进入体循环，避免药物在口服过程中可能遇到的任何吸收和首过障碍。 送货。最后，经皮给药避免了用注射器针刺穿皮肤，消除了疼痛和患者就诊。 给一位医生。在季节性和大流行性流感暴发期间，Zan的经皮给药是可取的，因为 大量患者可以得到治疗，疾病的传播也可以得到控制。 该提案的第二阶段将涉及Zan MN配方的优化和放大 以及随后在小型猪身上的药代动力学试验和在雪貂身上的疗效试验。人体剂量预测将 来自模拟引导的PK/PD建模和中空纤维感染模型的验证性研究 (HFIM)。启用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 研究以及第一阶段临床开发计划将在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的经皮给药方法，并展示了 有效性、PK和临床前安全性数据准备好打开IND应用程序。我们已经组建了一支专家团队 顾问和合作者，以确保成功完成本研究计划。

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.