A High Efficiency Corticosteroid Dry Powder Inhaler for Pediatric Use

描述(申请人提供)：哮喘是一种慢性呼吸道疾病，对患者和社会造成全球性的人类和经济负担。哮喘的治疗主要包括吸入皮质类固醇和支气管扩张剂，这使成年人在患病的情况下仍能正常工作。小气道炎在儿童哮喘的发病机制中特别重要，因此使用吸入皮质类固醇有效地靶向肺的这一区域的能力是重要的。目前向幼儿提供皮质类固醇的选择包括笨重的雾化制剂和口服糖浆，但这些针对小气道的方法效率低下，导致全身暴露于皮质类固醇的不必要数量。Savara开发了一项新技术，将儿童最常用的吸入皮质类固醇布地奈德重新配制成纳米团状干粉，由空气动力学中值尺寸为1-2.5米的颗粒组成，是有效输送到远端呼吸道的理想药物。此外，由于载体物质的消除，这些制剂具有更好的溶解性，并且由几乎纯的布地奈德组成。Savara的粉末技术将与一种新型吸入器设备相结合，当患者达到足以将药物输送到深肺的吸入流速时，该设备会以电子方式触发雾化。Savara的高性能吸入粉与这种对儿童的特殊吸入物不敏感的“儿科吸入器”相结合，将是儿科哮喘治疗的一大进步。这项建议的第一个目标是使用两种不同的工艺，即溶剂扩散和珠磨，优化Savara的初步布地奈德纳米簇配方。系统的实验将考察药物在溶液中的浓度、溶液在非溶剂中的进料速度、混合程度以及辅料的用途、性质和浓度。或者，对于微珠研磨过程，将评估关键变量，例如研磨介质直径、悬浮液中的药物浓度、研磨过程中的剪切力、研磨时间以及辅料的使用、性质和浓度。在目标2中，通过目标1选择的工艺生产的布地奈德纳米簇粉末将被填充到铝箔水泡中，并将通过使用模拟儿童吸入模式的条件的级联冲击器研究来评估由儿科吸入器提供的纳米簇制剂的气雾剂性能。在目标3中，将分三个小批次生产成功的制剂，并进行稳定性研究。在为临床试验做准备时，将记录布地奈德纳米簇儿童吸入器系统的IND气雾剂性能，包括粉末和填充物的批次重现性，以及稳定性研究的结果。 公共卫生相关性：小气道炎在儿童哮喘的发病机制中特别重要，因此有效地针对这一肺部区域的能力非常重要。目前向6岁儿童提供皮质类固醇的选择包括笨重的雾化制剂和口服糖浆，但这些针对小气道的方法效率低下，导致全身暴露于皮质类固醇的不必要数量。Savara建议应用其纳米簇技术将布地奈德重新配制成一种高效的吸入粉，与一种特殊的儿科吸入器结合使用，可以有效治疗儿童哮喘的呼吸道炎症，减少全身类固醇暴露，大大减少给药时间。

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.