A High Efficiency Corticosteroid Dry Powder Inhaler for Pediatric Use

描述（由申请人提供）：哮喘是一种慢性呼吸道疾病，对患者和社会造成全球人类和经济负担。哮喘治疗主要包括吸入皮质类固醇和支气管扩张剂，这些药物使成年人在患有哮喘的情况下仍能正常工作。小气道炎症在儿童哮喘发病机制中尤为重要，因此吸入皮质类固醇有效靶向肺这一区域的能力非常重要。目前用于给小孩注射皮质类固醇的方法包括繁琐的喷雾器配方和口服糖浆，但这些针对小气道的方法效率低下，导致不必要的全身暴露于皮质类固醇。Savara开发了一种新技术，将儿童最常用的吸入皮质类固醇布地奈德重新配制成一种纳米簇干粉，该干粉由空气动力学尺寸中值为1-2米的颗粒组成，非常适合有效地输送到远端气道。此外，由于消除了载体物质，该制剂具有更好的溶解度，并且几乎由纯布地奈德组成。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，该吸入器会电子触发雾化。Savara的高性能吸入粉末与这种对儿童特殊吸入特性不敏感的“儿科吸入器”的结合，即小体积吸入可变力和持续时间，将是儿科哮喘治疗的重大进步。本提案的第一个目标是使用两种不同的工艺，溶剂扩散和珠磨来优化Savara的初步布地奈德纳米团簇配方。系统实验考察溶液中药物浓度、溶液向非溶剂的进料速度、混合程度、辅料的使用、性质和浓度等因素的影响。另外，对于珠磨工艺，关键变量，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、研磨持续时间以及辅料的使用、性质和浓度，将被评估。在Aim 2中，由Aim 1选择的工艺生产的布地奈德纳米簇粉末将填充到铝箔水泡中，儿科吸入器提供的纳米簇配方的气溶胶性能将通过级联冲击研究进行评估，该研究使用模拟幼儿吸入模式的条件。在目标3中，成功的制剂将分三个小批量生产，并将进行稳定性研究。布地奈德纳米簇儿童吸入器系统的ind雾化性能，包括粉末和填料的批量可重复性，以及稳定性研究的结果将被记录下来，为临床试验做准备。

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.