Microneedle Delivery of Zanamivir for Treatment of Influenza Infections

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，扎那米韦(瑞乐沙®)仍保持高度活性 抗奥司他韦耐药流感病毒株，但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。 经皮微针给药策略在抗病毒，特别是抗流感市场中的应用 为大量未得到满足的医疗需求提供许多解决方案，并代表了一种有吸引力的市场进入战略。 与其他给药系统相比，透皮给药系统提供了许多改进。补丁不会 要求吞咽，消除口服副作用。通过皮肤的渗透使药物直接进入皮肤 并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。在流感暴发期间，Zan的经皮传递是可取的，因为大量的 可以联系到患者。 该提案的第一阶段部分将涉及原型补丁的配方优化和后续 小鼠体内药代动力学和药效试验。这项建议的最终研究将是皮肤毒理学研究 目的：评估兔最后贴片的皮肤刺激性。 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和初步临床前安全性数据准备好完成临床前开发活动，从而导致 一个Ind的开业。我们已经组建了一支由专家顾问和合作者组成的团队，以确保成功 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. 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, zanamivir (Relenza®) remains highly active against oseltamivir-resistant influenza strains, but 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 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 an influenza outbreak, as large numbers of patients can be reached. The Phase I portion of this proposal will involve formulation optimization of the prototype patch and subsequent pharmacokinetic and efficacy testing in mice. The final study for this proposal will be a dermatotoxicology studies to assess skin irritation of the final patches in rabbits. The end result of this work will be a novel, transdermal delivery approach for zanamivir with demonstrated efficacy, PK and initial preclinical safety data ready to complete preclinical development activities leading to the opening of an IND. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.