Microneedle Delivery of Zanamivir for Treatment of Influenza Infections

扎那米韦微针治疗流感感染

• 批准号: 9438857
• 负责人: Elke Lipka
• 金额: $ 28.48万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9438857
• 关键词: Adamantane; Address; Adoption; Adverse effects; Animals; Antiviral Agents; Asthma; Biological Availability; Birds; Blood Circulation; Caliber; Categories; Cessation of life; Contract Services; Correlation Studies; Crystallization; Data; Deglutition; Development; Devices; Diffuse; Dose; Drug Kinetics; Elderly; Ensure; Epidemic; Excipients; Family; Family suidae; Formulation; Funding; Future; Grant; Human; Hydrogels; In Vitro; Influenza; Inhalation; Inhalators; Investigational Drugs; Investigational New Drug Application; Length; Mammals; Manufactured Supplies; Medical; Methods; Mus; National Institute of Allergy and Infectious Disease; Needles; Neuraminidase inhibitor; Oral; Orthomyxoviridae; Oryctolagus cuniculus; Oseltamivir; Painless; Pathogenicity; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physicians; Population; Preventive measure; Production; Property; Puncture procedure; RNA Viruses; Regimen; Research; Research Design; Resistance; Respiratory System; Risk; Route; Safety; Skin; Sodium Chloride; Solubility; Solvents; Syringes; System; Testing; Therapeutic; Time; Toxicology; Universities; Utah; Vaccination; Vaccines; Virus; Visit; Work; absorption; anti-influenza; anti-influenza drug; aqueous; biothreat; design; driving force; economic impact; effective therapy; efficacy study; efficacy testing; flu; in vivo; influenza epidemic; influenza outbreak; influenzavirus; mortality; novel; pain patient; pandemic disease; pre-clinical; preclinical development; preclinical efficacy; preclinical safety; prevent; prototype; research clinical testing; resistant strain; respiratory; screening; seasonal influenza; skin barrier; skin irritation; zanamivir

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.

抽象的 每年流感流行都会袭击数百万人，导致多达 50 万人死亡。死亡大部分由 季节性流感病毒<0.03%，但在年轻人和老年人群中死亡率很高。 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 预计造成的负面经济影响超过 1500 亿美元。流感病毒属于 NIAID C 类 优先生物威胁，其特征是一种易于获得和传播的新兴媒介。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，流感治疗 仅有些效果，并且某些流感病毒株对目前市售的疗法具有抗药性， 金刚烷类和神经氨酸酶抑制剂达菲®。然而，扎那米韦 (Relenza®) 仍保持高度活性 针对奥司他韦耐药的流感病毒株，但其治疗效果受到其传播途径的严重限制 通过口腔吸入给药，这使得它不适合呼吸系统受损的患者 系统。因此，正如我们在此建议的那样，开发扎那米韦的新型给药替代方案有望 解决重大的未满足的医疗需求。 透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多种解决方案，并代表了一种有吸引力的市场进入策略。 透皮递送系统比其他递送系统提供了许多改进。补丁没有 需要吞咽，消除口服副作用。透过皮肤渗透，让药物直接进入体内 体循环并避免药物口服时可能遇到的任何吸收和首过障碍 送货。最后，透皮给药避免了注射器针头刺穿皮肤，从而消除了疼痛和患者就诊 给医生。在流感爆发期间，ZAN 的透皮给药是可取的，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贴剂的配方优化以及后续 小鼠药代动力学和功效测试。该提案的最终研究将是皮肤毒理学研究 评估最终贴片对兔子的皮肤刺激。 这项工作的最终结果将是扎那米韦的一种新颖的透皮给药方法，并已被证明 功效、PK 和初始临床前安全性数据已准备好完成临床前开发活动，从而实现 IND 的开放。我们组建了一支由专家顾问和合作者组成的团队，以确保成功 完成本研究计划。