Novel, Self-Applied MicroArray Patch (MAP) of Zanamivir for Treatment of the Flu

摘要 每年流感流行袭击数百万人，造成多达50万人死亡。造成的死亡人数 季节性流感病毒的感染率<0.03%，但在年轻人和老年人中死亡率很高。 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 负面经济影响估计超过1500亿美元。由于疗效不完全， 目前的疫苗，有效的药物治疗是必要的。目前，流感的治疗只是在一定程度上 有效，并且一些流感毒株对目前市售的治疗剂、金刚烷和 神经氨酸酶抑制剂Tamiflu®。然而，尽管扎那米韦（ZAN，Relenza®）对抗病毒药物仍然具有高度活性， 奥司他韦耐药流感病毒株，其治疗效果受到其给药途径的严重限制， 口服吸入，这使得它不适合呼吸系统受损的患者。因此，我们认为， 正如我们在这里提出的，开发一种新的ZAN交付替代品，有望解决一个重大的未满足的问题。 医疗需求。 经皮给药提供了许多优于其他给药系统的改进。药物直接进入 体循环、绕过口服递送的典型吸收和首过屏障。它避免皮肤 通过注射器针头穿刺，消除了疼痛和患者对临床医生的访问。ZAN的经皮递送可 在流感爆发期间能够接触到大量患者，这将特别重要 鉴于COVID-19疫情持续期间增加的风险。虽然ZAN本身无法穿过人体皮肤， 屏障，微阵列贴片（MAP）增强的透皮给药是一种优雅，有效， 以及增加包括ZAN在内的许多药物的皮肤渗透的无痛方法。我们的新型药物装置 组合产品TSR-066由可溶胀的微针阵列组成，其将持续递送ZAN 从一个特殊配方的水库超过5天。此快速通道SBIR提案将支持优化 MAP，重点关注施源器组件和I期临床试验用品的后续制造 study.我们已与FDA就开启IND所需的临床前研究达成一致， 以及I期临床开发计划和505（B）2监管策略。除了有 在这里提出的实验工作中，我们正在为TSR-066开发一个强大的IP扩展策略，以及 未来的候选产品将从支持MAP的交付中受益。 这项工作的最终结果将是一种新的ZAN透皮给药方法，这将扩大其范围 用于禁忌Relenza®的患者组，并允许对两种患者进行简单的ZAN给药 治疗和预防流感。我们组建了一个专家顾问和合作者团队，以确保 顺利完成了这项研究计划。

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. 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 (ZAN, 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 ZAN as we propose here, is poised to address a significant unmet medical need. Transdermal drug delivery offers a number of improvements over other delivery systems. The drug directly enters the systemic circulation, circumventing absorption and first-pass barriers typical for oral delivery. It avoids skin puncture by syringe needles, eliminating pain and patient visits to a clinician. Transdermal delivery of ZAN could allow large numbers of patients to be reached during an influenza outbreak, which will be particularly important in light of the added risk during the ongoing COVID-19 pandemic. While ZAN itself cannot cross the human skin barrier at therapeutic rates, MicroArray Patch (MAP) - enhanced transdermal delivery is an elegant, efficient, and painless method for increasing the skin permeation of many drugs, including ZAN. Our novel drug-device combination product, TSR-066, consists of a swellable microneedle array, which will continuously deliver ZAN from a specially formulated reservoir over 5 days. This Fast-Track SBIR proposal will support optimization of the MAP with a focus on the applicator component and subsequent manufacturing of supplies for the Phase I clinical study. We have obtained agreement with the FDA on the preclinical studies needed in order to open the IND, as well as on the Phase I clinical development plans and the 505(b)2 regulatory strategy. In addition to the experimental work proposed here, we are developing a robust IP expansion strategy for TSR-066, as well as future product candidates that stand to benefit from MAP-enabled delivery. The end result of this work will be a novel, transdermal delivery approach for ZAN, which will expand its reach into patient groups for which Relenza® is contraindicated and allow for simple administration of ZAN for both treatment and prevention of the flu. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.