Treatment of NTM Respiratory Infections with Inhaled Drug Delivery

吸入给药治疗 NTM 呼吸道感染

• 批准号: 9347149
• 负责人: Brian N Hansen
• 金额: $ 30万
• 依托单位: AEROPHASE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347149
• 关键词: Adverse effects; Aerosols; Alveolar; Amikacin; Antibiotic Therapy; Antibiotics; Beclomethasone; Breathing; Caliber; Clarithromycin; Complex; Contracts; Cutaneous; Data; Deposition; Development; Devices; Disease; Dose; Drug Delivery Systems; Drug Formulations; Fishes; Formulation; Genus Mycobacterium; Goals; Graph; Hawaii; High Prevalence; Hydrophobicity; Infection; Inhalators; Injection of therapeutic agent; Lung; Lung diseases; Macrolides; Mandatory Reporting; Medical Device; Medicine; Metered Dose Inhaler Device; Methods; Multiple drug resistant Mycobacteria Tuberculosis; Mycobacterium avium; National Institute of Allergy and Infectious Disease; Nebulizer; Oral; Organ; Pharmaceutical Preparations; Prevalence; Pulmonary Tuberculosis; Resistance; Respiratory Tract Infections; Site; Small Business Innovation Research Grant; Solubility; Source; Swimming Pools; Technology; Testing; Time; Toxic effect; Water; Woman; Work; base; cost; effective therapy; efficacy study; human old age (65+); in vivo; innovation; interest; meetings; mouse model; mycobacterial; non-tuberculosis mycobacteria; novel therapeutics; pressure; propellant; respiratory; stratospheric ozone; submicron; systemic toxicity; tuberculosis treatment

Project Summary/Abstract (Description) Significance: Non-tuberculous mycobacteria (NTM) respiratory infections is increasing across the globe. In the US, in those over 65 years-old, annual prevalence of pulmonary NTM disease increased significantly from 20 to 47 cases/100,000 between 1997-2007 with Hawaii having the highest prevalence at 396 cases/100,000. Pulmonary NTM is 1.4 times more common in women. These numbers are likely underestimated because of a lack of mandatory reporting in the U.S. Treatment of non-tuberculous mycobacterial lung disease is challenging for several reasons including the relative resistance to currently available drugs and the difficulty in tolerating prolonged treatment with multiple drugs. The only oral drugs with reliable activity against M. abscessus complex an NTM are the macrolides and clofazimine. Similar to that for M. avium complex, clofazimine was found to synergize with clarithromycin or amikacin against M. abscessus Clofazimine is an attractive agent for treatment of NTM respiratory infections including M. abscessus but cutaneous and internal organ accumulation from high oral doses cause significant toxicity. High oral doses are required to reach effective concentrations in the lungs. Inhaled doses of clofazimine have the potential to reach immediate treatment concentrations in the lungs with inhaled low doses that do not have significant systemic toxicity. Preliminary Data: Aerophase has recently demonstrated that innovative aerosol formulations of clofazimine with a new type of aerosol drug inhaler can treat TB respiratory infections without side effects from systemic toxicity. The new clofazimine formulation and aerosol device has demonstrated sustained pulmonary treatment concentration and an aerosol size range that can target the entire lung with clofazimine even alveolar regions. The Aerophase inhaled aerosol delivery method holds great promise to mitigate toxicity and allow for safe clofazimine administration directly targeted to the site of infection. Specific Aims: The first aim of this project is to treat NTM respiratory infections with inhaled clofazimine much more effectively than oral clofazimine with much lower inhaled dose. The second aim is to develop a small pocket sized metered dose inhaler with drug formulation, aerosol size, and dose optimized to treat NTM respiratory infections. The third aim will test in-vivo efficacy of inhaled clofazimine in combination with other drugs.

项目摘要/摘要（描述） 意义：非结核分枝杆菌 (NTM) 呼吸道感染正在增加 地球仪。在美国，65 岁以上人群中，肺 NTM 疾病的年患病率 1997 年至 2007 年间，病例数从 20 例/10 万例大幅增加至 47 例/10 万例，其中夏威夷州 发病率最高为 396 例/100,000。肺 NTM 的发生率是其 1.4 倍 女性。由于缺乏强制报告，这些数字可能被低估 美国治疗非结核分枝杆菌肺病对一些人来说具有挑战性 原因包括对现有药物的相对耐药性以及治疗的困难 耐受多种药物的长期治疗。唯一具有可靠活性的口服药物 对抗脓肿分枝杆菌复合体的 NTM 是大环内酯类和氯法齐明。类似于 M. avium 复合物、氯法齐明被发现可与克拉霉素或阿米卡星协同对抗 脓肿分枝杆菌 氯法齐明是治疗 NTM 呼吸道感染的一种有吸引力的药物 包括脓肿分枝杆菌，但高剂量口服后会在皮肤和内脏器官中积聚 引起显着的毒性。需要高口服剂量才能达到有效浓度 肺。吸入剂量的氯法齐明有可能达到立即治疗的效果 吸入低剂量时肺部的浓度不会产生显着的全身毒性。 初步数据：Aerophase 最近证明，创新的气雾剂配方 氯法齐明配合新型气雾药物吸入器可治疗结核性呼吸道感染，无需 全身毒性的副作用。新的氯法齐明制剂和气雾剂装置具有 证明了持续的肺部治疗浓度和气溶胶尺寸范围可以 使用氯法齐明靶向整个肺部，甚至肺泡区域。 Aerophase 吸入气雾剂 递送方法有望减轻毒性并实现安全的氯法齐明 直接针对感染部位进行给药。 具体目标：该项目的首要目标是通过吸入治疗 NTM 呼吸道感染 氯法齐明比口服氯法齐明更有效，且吸入剂量低得多。 第二个目标是开发一种具有药物配方的小型袖珍定量吸入器， 气雾剂大小和剂量经过优化以治疗 NTM 呼吸道感染。 第三个目标将测试吸入氯法齐明与其他药物联合使用的体内疗效。