Microneedle Delivery of Zanamivir for Treatment of Influenza Infections

摘要 每年流感流行都会袭击数百万人，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。流感病毒属于NIAID C类 优先生物威胁，其特点是一种容易获得和传播的新制剂。由于 目前疫苗的效力不完全，有效的药物治疗是必要的。目前，流感治疗 只是有些效果，并且一些流感病毒株对目前市售的治疗剂有抗性， 金刚烷和神经氨酸酶抑制剂Tamiflu®。然而，扎那米韦（Relenza®）仍然具有高度活性， 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。 通过口服吸入给药，这使得其不适合具有受损的呼吸系统疾病的患者。 系统因此，我们在此提出的扎那米韦新的递送替代品的开发， 解决了严重未满足的医疗需求。 经皮微针递送策略在抗病毒，特别是抗流感市场中的应用 为大量未满足的医疗需求提供了许多解决方案，并代表了一个有吸引力的市场进入战略。 经皮递送系统提供了优于其它递送系统的许多改进。补丁不会 需要吞咽，消除口腔副作用。通过皮肤的渗透使药物直接进入 避免口服药物可能遇到任何吸收和首过障碍 交付.最后，透皮给药避免了注射器针头刺穿皮肤，消除了疼痛和患者就诊 一个医生。在流感爆发期间，ZAN的经皮递送是期望的，因为大量的流感病毒感染了ZAN。 患者可以到达。 该提案的第一阶段部分将涉及原型贴片的配方优化以及后续 在小鼠中的药代动力学和功效测试。本提案的最终研究将是皮肤毒理学研究 以评估家兔中最终贴剂的皮肤刺激性。 这项工作的最终结果将是一种新的扎那米韦透皮给药方法， 有效性、PK和初始临床前安全性数据，准备完成临床前开发活动， 我们已经组建了一个专家顾问和合作者团队，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.