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.

摘要