High Efficiency Inhalation Delivery of Tobramycin for Children with Cystic Fibrosis

妥布霉素高效吸入治疗囊性纤维化儿童

• 批准号: 9236359
• 负责人: Michael Hindle
• 金额: $ 48.98万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-21 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236359
• 关键词: 10 year old; 2 year old; 6 year old; Adult; Aerosols; Age; Antibiotics; Bacteria; Breathing; Cannulas; Child; Childhood; Chronic; Coupled; Cystic Fibrosis; Data; Deposition; Development; Devices; Dimensions; Dose; Drug Delivery Systems; Excipients; Formulation; Goals; Growth; In Vitro; Infection; Inhalation Therapy; Inhalators; Life; Liquid substance; Lung; Lung diseases; Mannitol; Morbidity - disease rate; Mucous body substance; Nebulizer; Nose; Outcome; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Population; Powder dose form; Pseudomonas aeruginosa; Pulmonary Fibrosis; Quality of life; Recurrence; Respiratory physiology; Safety; Sputum; System; Techniques; Technology; Testing; Therapeutic; Time; Tobramycin; Wettability; airway surface liquid; antimicrobial; bacterial resistance; capsule; children with cystic fibrosis; comparative efficacy; compliance behavior; cystic fibrosis patients; design; drug inhalation; effective therapy; fine particles; improved; mortality; mucoid; novel strategies; particle; pediatric patients; preclinical development; retinal rods; simulation

Treatment of Pseudomonas aeruginosa (Pa) and other lung infections in pediatric cystic fibrosis (CF) patients currently relies on adult aerosol delivery devices, and effective dry powder inhaler platforms are not available for patients under 6 years of age. While treatment with inhaled antibiotics is considered safe and effective, CF patients continue to progress to chronic infections and the time burden of treatment is high, especially with the use of nebulized solutions in children under 6 years of age. This project will develop a new inhalable dry powder tobramycin formulation and delivery device combination intended for pediatric patients in the age range of 2-10 years that seeks to lower the inhaled powder burden to a single capsule delivered with high efficiency. For effective and targeted lung delivery, an excipient enhanced growth (EEG) approach will be implemented where combination submicrometer particles of tobramycin and mannitol (MN) are formed by spray drying. The initially small size of the aerosol allows for effective deep lung delivery, even in diseased lungs, and the inclusion of MN as the hygroscopic excipient results in aerosol size increase within the lungs and targeted deposition. A simple active dry powder inhaler (DPI) system will be developed that implements new three-dimensional (3D) rod array technology, which has previously been shown to effectively deaggregate carrier-free powders at low flows required for pediatric applications. The initial particle size and hygroscopic excipient content will be designed to produce controlled aerosol size increase and deposition, thereby providing a uniform concentration of tobramycin in airway surface liquid. To develop this new approach, three Specific Aims are proposed: Specific Aim 1: Develop an inhaled tobramycin excipient enhanced growth (TOB-EEG) formulation that is stable and provides high dispersion when coupled with an inline dry powder inhaler (DPI) system. Specific Aim 2: Apply a concurrent computational fluid dynamics (CFD) and in vitro approach to develop and optimize a high-efficiency and high-dose active DPI system for pediatric CF patients across a range of ages. Specific Aim 3: Predict and optimize regional lung delivery concentrations of tobramycin in lung airway surface liquid using CFD, and evaluate the effects of tobramycin and excipient concentrations on in vitro sputum penetration and antimicrobial activity. This newly proposed TOB-EEG inhalation therapy will allow for efficient DPI use in pediatric patients < 6 years old for the first time. Development of a convenient DPI platform will improve patient compliance and help to promote early eradication therapy of newly identified Pa infections. The newly developed TOB-EEG formulation will significantly increase aerosol delivery to the small airways, provide significantly more uniform antibiotic concentration throughout the airways, and improve penetration of the antibiotic through the mucus to improve bacterial eradication.

儿科囊性纤维化（CF）中铜绿假单胞菌（Pa）和其他肺部感染的治疗 患者目前依赖于成人气雾剂递送装置，而有效的干粉吸入器平台并不 适用于6岁以下的患者。虽然吸入抗生素治疗被认为是安全的， 有效，CF患者继续进展为慢性感染，治疗的时间负担很高， 尤其是在6岁以下儿童中使用雾化溶液。 本项目将开发一种新的可吸入干粉妥布霉素制剂和给药装置 预期用于2-10岁儿童患者的复方制剂，旨在降低吸入的 粉末负载到单个胶囊中，以高效率输送。为了有效和有针对性的肺部递送， 将实施赋形剂增强生长（EEG）方法，其中组合亚微米颗粒 妥布霉素和甘露醇（MN）的混合物通过喷雾干燥形成。气溶胶的初始小尺寸允许 有效的肺深部递送，甚至在患病的肺中，以及包含MN作为吸湿性赋形剂 导致肺内的气溶胶尺寸增加和靶向沉积。一种简易活性干粉吸入器 (DPI)将开发实现新的三维（3D）棒阵列技术的系统， 先前已显示在儿科应用所需的低流速下可有效解聚无载体粉末 应用.将设计初始粒度和吸湿性辅料含量，以生产受控的 气溶胶尺寸增加和沉积，从而在气道中提供均匀的妥布霉素浓度 表面液体。为了发展这一新方法，提出了三个具体目标： 具体目标1：开发吸入妥布霉素赋形剂增强生长（TOB-EEG）制剂， 当与在线干粉吸入器（DPI）系统结合时，稳定并提供高分散性。 具体目标2：应用并行计算流体动力学（CFD）和体外方法， 为不同年龄的儿童CF患者优化高效、高剂量的主动DPI系统。 具体目标3：预测和优化妥布霉素在肺气道中的局部肺递送浓度 表面液体，并评估妥布霉素和赋形剂浓度对体外 痰渗透性和抗微生物活性。 这种新提出的TOB-EEG吸入疗法将允许在< 6岁的儿科患者中有效使用DPI 老了，第一次。开发方便的DPI平台将提高患者依从性，并有助于 促进新发现的Pa感染的早期根除治疗。新开发的TOB-EEG 制剂将显著增加气雾剂递送到小气道，提供显著更多的 均匀的抗生素浓度在整个气道，并提高抗生素的渗透 通过粘液来促进细菌的根除。