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: 10200865
• 负责人: Michael Hindle
• 金额: $ 47.57万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200865
• 关键词: 10 year old; 2 year old; 3-Dimensional; 6 year old; Adult; Aerosols; Age; Antibiotics; Bacteria; Cannulas; Child; Childhood; Coupled; Cystic Fibrosis; Cystic Fibrosis sputum; Data; Deposition; Development; Devices; Dose; Drug Delivery Systems; Excipients; Formulation; Goals; Growth; In Vitro; Infection; Inhalation; Inhalation Therapy; Inhalators; Life; Liquid substance; Lung; Lung diseases; Lung infections; Mannitol; Morbidity - disease rate; Mucous body substance; Nebulizer; Nose; Outcome; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Population; Powder dose form; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Fibrosis; Quality of life; Recurrence; Rod; Safety; Sputum; System; Techniques; Technology; Testing; Therapeutic; Time; Tobramycin; Wettability; airway surface liquid; antimicrobial; bacterial resistance; capsule; children with cystic fibrosis; chronic infection; comparative efficacy; compliance behavior; cystic fibrosis infection; cystic fibrosis patients; design; drug inhalation; effective therapy; fine particles; improved; lung preservation; mortality; mucoid; novel strategies; particle; pediatric patients; preclinical development; pulmonary function; 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.

儿童囊性纤维化合并铜绿假单胞菌等肺部感染的治疗 患者目前依赖成人气雾剂输送设备，而有效的干粉吸入器平台并不是 适用于6岁以下儿童。虽然吸入抗生素治疗被认为是安全的和 有效的，CF患者继续进展为慢性感染，治疗的时间负担很高， 特别是在6岁以下儿童中使用雾化溶液。 本项目将开发一种新型可吸入干粉妥布霉素制剂和给药装置 为2-10岁的儿科患者设计的联合用药，旨在降低吸入 粉料输送至单粒胶囊，效率高。为了有效和有针对性地进行肺部给药， 辅料增强生长(EEG)方法将在结合亚微米颗粒的情况下实施 妥布霉素和甘露醇(MN)的混合物是通过喷雾干燥形成的。气雾剂最初的小尺寸允许 有效的肺深部给药，即使是在患病的肺部，并将MN作为吸湿性赋形剂 结果导致肺内气溶胶尺寸增加和靶向沉积。一种简易活性干粉吸入器 将开发实现新的三维(3D)棒阵技术的(DPI)系统，该系统具有 以前被证明在儿科所需的低流量下有效地解聚无载体粉末 申请。初始颗粒大小和吸湿性赋形剂含量将设计为生产受控 气雾剂尺寸增大和沉积，从而在呼吸道中提供均匀浓度的妥布霉素 表面液体。为了开发这一新方法，提出了三个具体目标： 具体目标1：开发一种吸入型妥布霉素辅料促进生长(TOB-EEG)配方 与直列式干粉吸入器(DPI)系统配合使用时，性能稳定，分散性高。 具体目标2：应用并行计算流体动力学(CFD)和体外方法开发和 为不同年龄段的儿童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内的局部给药浓度 用CFD计算表面液，并评价妥布霉素和赋形剂浓度对体外实验的影响 痰渗透和抗菌活性。 这一新提出的TOB-EEG吸入疗法将允许在6年内有效地使用DPI治疗儿科患者。 第一次上了年纪。开发方便的DPI平台将提高患者的依从性，并有助于 促进新发现的PA感染的早期根除治疗。新研制的TOB-EEG 配方将显著增加气雾剂向小气道的输送，提供明显更多 使抗生素在呼吸道内浓度均匀，并提高抗生素的渗透率 通过粘液来提高细菌的清除能力。

项目成果

Dry powder aerosol containing muco-inert particles for excipient enhanced growth pulmonary drug delivery.

• DOI: 10.1016/j.nano.2020.102262
• 发表时间: 2020-10
• 期刊: Nanomedicine : nanotechnology, biology, and medicine
• 作者: Chai G;Hassan A;Meng T;Lou L;Ma J;Simmers R;Zhou L;Rubin BK;Zhou QT;Longest PW;Hindle M;Xu Q
• 通讯作者: Xu Q

Evaluation of the Polyhedral Mesh Style for Predicting Aerosol Deposition in Representative Models of the Conducting Airways.

用于预测传导气道代表性模型中气溶胶沉积的多面体网格样式的评估。

• DOI: 10.1016/j.jaerosci.2021.105851
• 发表时间: 2022
• 期刊: Journal of aerosol science
• 影响因子: 4.5
• 作者: Thomas,MorganL;Longest,PWorth
• 通讯作者: Longest,PWorth

Recommendations for Simulating Microparticle Deposition at Conditions Similar to the Upper Airways with Two-Equation Turbulence Models.

• DOI: 10.1016/j.jaerosci.2018.02.007
• 发表时间: 2018-05
• 期刊: Journal of aerosol science
• 影响因子: 4.5
• 作者: Bass K;Longest PW
• 通讯作者: Longest PW

Airway mucus in pulmonary diseases: Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers.

• DOI: 10.1016/j.ijpharm.2023.122661
• 发表时间: 2023-02
• 期刊: International journal of pharmaceutics
• 影响因子: 5.8
• 作者: R. Pangeni;Tuo Meng;Sagun Poudel;Divya Sharma;Hallie Hutsell;Jonathan Ma;B. Rubin;Worth Longest;M. Hindle;Qingguo Xu