Microneedle Delivery of Zanamivir for Treatment of Influenza

扎那米韦微针治疗流感

• 批准号: 10132966
• 负责人: Elke Lipka
• 金额: $ 95.22万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132966
• 关键词: Acute; Adamantane; Address; Animals; Antiviral Agents; Blood Circulation; Categories; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical Virology; Communicable Diseases; Communities; Data; Deglutition; Development; Development Plans; Disease; Dose; Drug Kinetics; Elderly; Ensure; Epidemic; Family suidae; Feedback; Ferrets; Fiber; Formulation; Horns; Human; Infection; Influenza; Inhalation; Investigational Drugs; Investigational New Drug Application; Lung; Medical; Methods; Miniature Swine; Modeling; National Institute of Allergy and Infectious Disease; Needles; Neuraminidase inhibitor; Oral; Oseltamivir; Painless; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Physicians; Population; Powder dose form; Puncture procedure; Regimen; Research; Resistance; Respiratory System; Route; Skin; Syringes; System; Testing; Therapeutic; Time; Toxicology; Transdermal substance administration; Treatment Efficacy; Vaccination; Vaccines; Validation; Virus; Visit; Work; absorption; anti-influenza; biothreat; clinical development; economic impact; effective therapy; efficacy study; efficacy testing; flu; in vivo; influenza epidemic; influenza infection; influenza outbreak; influenza virus strain; influenzavirus; meetings; mortality; novel; pain patient; pandemic disease; pandemic influenza; patient population; pharmacodynamic model; phase III trial; pre-clinical; preclinical safety; preclinical study; prevent; product development; prototype; reduce symptoms; resistant strain; respiratory; scale up; seasonal influenza; side effect; simulation; skin barrier; skin irritation; transmission process; vaccine effectiveness; 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, 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.

抽象的 每年影响流行病的人数数百万，造成多达500,000人死亡。大多数人造成的死亡 季节性影响病毒<0.03％，但年轻人和老年人的死亡率显着。 当新的病原影响力进入人群时，大流行可能会杀死数千万人 经济影响负面影响估计超过1500亿美元。流感病毒是niAID类别C 优先的Biothreat，其特征是一种新兴剂，容易获得和传播。由于 当前疫苗的有效性不完全，有效的药物治疗是必要的。目前，有影响力的治疗 只有某种有效的效果，并且某些影响力菌株对当前销售的疗法有抵抗力， Adamantanes和Neurominidase抑制剂Tamiflu®。但是，尽管Zanamivir（Relenza®）仍然很高 积极反对抗奥斯塔米维尔的影响者，其治疗影响受到其途径的严重限制 通过口服吸入给药，这使其不适合患有呼吸的患者 系统。因此，正如我们在这里提出的那样，开发Zanamivir的新型交付替代方案被毒成 满足巨大的未满足医疗需求。 将透皮微针（MN）递送策略应用于抗病毒，尤其是抗炎性 市场为大量未满足的医疗需求提供了许多解决方案，代表着一个有吸引力的市场进入 战略。透皮输送系统比其他交付系统提供了许多改进。补丁 不需要吞咽，消除口腔副作用。通过皮肤渗透使药物可以直接 输入系统圈，避免药物可能会遇到口服的任何滥用和首次障碍 送货。最后，透皮递送避免了注射器针的皮肤穿刺，消除了疼痛和患者就诊 身体。在季节性和大流行有影响力爆发期间，Zan的透皮传递是可取的，如 可以治疗大量患者，并且可以控制疾病的传播。 该提案的第二阶段部分将涉及ZAN MN公式的公式优化和扩展 以及随后在Minipigs中进行的药代动力学测试，并在雪貂中进行有效测试。人剂量预测将 源自模拟引导的PK/PD建模和空心纤维感染模型中的确认研究 （HFIM）。辅助皮肤毒理学研究将完成临床前数据包。都是临床前 研究以及I期临床开发计划将在一次预科会议上提交FDA。 这项工作的最终结果将是Zanamivir的新颖的，透皮传递的方法 功效，PK和临床前安全数据准备打开IND应用程序。我们组建了一个专家团队 顾问和合作者确保成功完成本研究计划。