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

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。由于不完全的药效 目前的疫苗，有效的药物治疗是必要的。目前，流感的治疗只是一小部分 有效，一些流感病毒株对目前市场上销售的治疗药物、金刚烷胺和 神经氨酸酶抑制剂达菲®。然而，当扎那米韦(Zan，Relenz®)仍高度活跃于 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，通过 口服吸入，这使得它不适合呼吸系统受损的患者。因此， 我们在此建议开发一种新的Zan交付替代方案，准备解决一个重大的未满足的问题 医疗需要。 与其他给药系统相比，经皮给药提供了许多改进。药物直接进入 体循环，绕过吸收和首次通过障碍，典型的口服给药。它能避开皮肤 通过注射器针头进行穿刺术，消除疼痛和患者就诊。赞可素的经皮给药 允许在流感爆发期间接触到大量患者，这将特别重要 鉴于新冠肺炎大流行期间增加的风险。而赞本身不能穿过人类的皮肤 在治疗率方面，微阵列贴片(MAP)增强型经皮给药是一种优雅、高效、 和无痛的方法，增加许多药物的皮肤渗透性，包括Zan。我们的新型药物装置 组合产品TSR-066由可膨胀的微针阵列组成，将持续提供Zan 从特殊配方的储水池中取出超过5天。此快速通道SBIR提案将支持优化 将重点放在第一阶段临床用品的涂抹器组件和后续制造上 学习。我们已与FDA就开设IND所需的临床前研究达成协议，因为 以及第一阶段临床开发计划和505(B)2监管战略。除 在这里提出的实验工作，我们正在为TSR-066开发一个健壮的IP扩展策略，以及 未来的候选产品将受益于地图启用的交付。 这项工作的最终结果将是Zan的一种新的经皮给药方法，这将扩大其覆盖范围 进入雷乐沙®禁忌症的患者组，并允许对这两个患者简单地使用Zan 流感的治疗和预防。我们已经组建了一支由专家顾问和合作者组成的团队，以确保 圆满完成这项研究计划。

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.