Microneedle Delivery of Zanamivir for Treatment of Influenza

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。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，虽然扎那米韦（Relenza®）仍然很高， 虽然它对奥司他韦耐药流感病毒株具有活性，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。 透皮微针（MN）递送策略在抗病毒，特别是抗流感， 市场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 进入体循环，避免口服药物可能遇到的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。在季节性和大流行性流感爆发期间，ZAN的经皮递送是理想的，因为 可以治疗大量患者，并控制疾病的传播。 该提案的第二阶段部分将涉及ZAN MN制剂的配方优化和规模扩大 随后在小型猪中进行药代动力学测试，并在雪貂中进行功效测试。人类剂量预测将 来自模拟指导的PK/PD建模和中空纤维感染模型中的验证性研究 （Haven't）。IND使能皮肤毒理学研究将完成临床前数据包。所有临床前 研究以及I期临床开发计划将在IND前会议期间提交给FDA。 这项工作的最终结果将是一种新的扎那米韦透皮给药方法， 有效性、PK和临床前安全性数据准备开启IND申请。我们召集了一个专家小组 顾问和合作者，以确保顺利完成这项研究计划。

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, 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.