A High Efficiency Corticosteroid Dry Powder Inhaler for Pediatric Use

儿童用高效皮质类固醇干粉吸入器

• 批准号: 8057330
• 负责人: Taneli Jouhikainen
• 金额: $ 18.41万
• 依托单位: SAVARA, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057330
• 关键词: 6 year old; Address; Adrenal Cortex Hormones; Adult; Aerosols; Aluminum; Area; Asthma; Breathing; Bronchodilator Agents; Budesonide; Bulla; Caliber; Child; Childhood; Childhood Asthma; Chronic; Clinical Research; Clinical Trials; Data; Devices; Diffusion; Disease; Distal; Dose; Drug Formulations; Economic Burden; Electronics; Engineering; Ensure; Evaluation; Excipients; Exposure to; Goals; Guidelines; Human; Inhalators; Lung; Lung diseases; Methods; Nature; Nebulizer; Oral; Pathogenesis; Patients; Pattern; Performance; Pharmaceutical Preparations; Population; Powder dose form; Preparation; Process; Reproducibility; Series; Simulate; Societies; Solubility; Solutions; Solvents; Steroids; Suspension substance; Suspensions; System; Technology; Time; airway inflammation; asthmatic airway; effective therapy; experience; feeding; improved; new technology; novel; particle; research study

DESCRIPTION (provided by applicant): Asthma is a chronic respiratory disease with a global human and economic burden on patients, and society. Asthma treatment mainly consists of inhaled corticosteroids and bronchodilators, which enable adult populations to function well despite the disease. Small airway inflammation is particularly important in the pathogenesis of asthma in children, and hence the ability to target this area of the lung efficiently with inhaled corticosteroids is of major importance. Current options for delivering corticosteroids to small children include cumbersome nebulizer formulations and oral syrups, but the inefficiency of these methods to target the small airways result in an unnecessary amount of systemic exposure to corticosteroids. Savara has developed a novel technology to reformulate the most commonly used inhaled corticosteroid in small children, budesonide, into a NanoCluster dry powder composed of particles ranging 1-2 5m in median aerodynamic size, which is ideal for effective delivery to the distal airways. In addition, the formulations have improved solubility, and are composed of almost pure budesonide due to the elimination of carrier substances. Savara's powder technology will be combined with a novel inhaler device that electronically triggers the aerosolization when the patient reaches an inhalation flow rate sufficient to deliver the drug to the deep lung. The combination of Savara's high performance inhalation powder with this "Pediatric Inhaler" that is not sensitive to the special inhalation profiles of small children, i.e. small volume of inhalation with variable force and duration, will be a major advance in pediatric asthma therapy. The first aim of this proposal is to optimize Savara's preliminary budesonide NanoCluster formulations using two different processes, solvent diffusion and bead milling. Systematic experiments will be conducted to investigate the effect of the drug concentration in solution, the feed rate of solution into non-solvent, the degree of mixing, and the use, nature and concentration of excipients. Alternatively, for the bead-milling process, key variables, such as milling media diameter, drug concentration in suspension, shear force during milling, duration of milling, and the use, nature, and concentration of excipients, will be evaluated. In Aim 2, budesonide NanoCluster powder, produced by the process selected as a result of Aim 1 will be filled into aluminum foil blisters and the aerosol performance of the NanoCluster formulation delivered by the Pediatric Inhaler will be evaluated through cascade impactor studies using conditions that simulate inhalation patterns in small children. In Aim 3, successful formulations will be produced in three small batches that will be subjected to stability studies. IND-enabling aerosol performance of the budesonide NanoCluster Pediatric Inhaler system, including batch-to-batch reproducibility of the powders and fillings, as well as the results of the stability studies will be documented in preparation for clinical trials. PUBLIC HEALTH RELEVANCE: Small airway inflammation is particularly important in the pathogenesis of asthma in children, and hence the ability to efficiently target this area of the lung efficiently is of high importance. Current options for delivering corticosteroids to small children (<6 years of age) include cumbersome nebulizer formulations and oral syrups, but the inefficiency of these methods to target the small airways result in an unnecessary amount of systemic exposure to corticosteroids. Savara proposes to apply its NanoCluster technology to reformulate budesonide into a highly efficient inhalation powder that in conjunction with a special pediatric inhaler allows effective treatment of the asthmatic airway inflammation in small children with reduced systemic steroid exposure and substantially reduced administration times.

描述（由申请人提供）：哮喘是一种慢性呼吸道疾病，对患者以及社会负担全球人类和经济负担。哮喘治疗主要由吸入的皮质类固醇和支气管扩张剂组成，这使成年人种群尽管疾病能够正常运作。小气道炎症在儿童哮喘的发病机理中尤为重要，因此，用吸入的皮质类固醇有效地靶向肺部的这一区域至关重要。当前向小孩提供皮质类固醇的选择包括繁琐的雾化器配方和口服糖浆，但是这些方法的效率低下以靶向小气道，导致不必要的全身性暴露于皮质类固醇。萨瓦拉（Savara）开发了一种新颖的技术，可以重新制定小孩（布德索尼）中最常用的吸入皮质类固醇，该技术由纳米簇干粉末组成，由颗粒组成的颗粒中位数中位空气动力学大小，这是有效送达远端气道的理想选择。另外，制剂具有提高的溶解度，并且由于消除了载体物质而由几乎纯的布德索尼组成。 Savara的粉末技术将与一种新型的吸入器设备结合使用，该设备将在患者达到足以将药物输送到深肺的吸入流量时以电子方式触发雾化。 Savara的高性能吸入粉与这种对小儿童的特殊吸入型分不敏感的“儿科吸入器”的结合，即用少量吸入和持续时间吸入的吸入量，将是儿科哮喘治疗的重大进展。该提案的第一个目的是使用两个不同的过程，即溶剂扩散和珠铣削来优化Savara的Budesonide纳米簇制定。将进行系统的实验，以研究药物浓度在溶液中的影响，溶液中的进料速率，无溶剂，混合程度以及赋形剂的使用，性质和浓度。另外，将评估循环过程的关键变量，例如铣削培养基直径，悬浮液中的药物浓度，铣削期间的剪切力，铣削持续时间以及摄取剂的使用，性质和浓度。在AIM 2中，由AIM 1选择的过程产生的布德索尼尼德纳米簇粉末将被填充到铝箔水泡中，并将使用模拟小儿童中吸入模式的条件来通过级联撞击器研究来评估小儿吸入器的纳米簇配方的气溶胶性能。在AIM 3中，将在三个小批处理中生产成功的配方，这将受到稳定研究。布德索德纳米簇的小儿吸入器系统的气溶胶性能，包括粉末和填充物的批量重现性，以及稳定性研究的结果，以准备临床试验。 公共卫生相关性：小气道炎症在儿童哮喘的发病机理中尤为重要，因此有效地有效地针对肺部的能力非常重要。当前向小儿童提供皮质类固醇的选择（<6岁）包括繁琐的雾化剂配方和口服糖浆，但是这些方法的效率低下，以瞄准小气道的效率导致不必要的全身暴露于皮质类固醇。 Savara建议将其纳米簇技术应用于高效的吸入粉末，并将其与特殊的儿科吸入器结合使用，可以有效治疗全身性类固醇暴露降低并大大减少给药时间的小儿童哮喘气道炎症。