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.

治疗小儿囊性纤维化 (CF) 中的铜绿假单胞菌 (Pa) 和其他肺部感染 患者目前依赖成人气雾剂输送装置，并且没有有效的干粉吸入器平台 适合 6 岁以下患者。虽然吸入抗生素治疗被认为是安全且有效的 有效，CF患者继续进展为慢性感染，治疗时间负担高， 尤其是 6 岁以下儿童使用雾化溶液时。 该项目将开发一种新型可吸入干粉妥布霉素制剂和输送装置 适用于 2-10 岁儿童患者的组合，旨在降低吸入 粉末负载到单个胶囊中，高效输送。为了有效和有针对性的肺部输送， 将实施辅料增强生长（EEG）方法，其中组合亚微米颗粒 妥布霉素和甘露醇(MN)通过喷雾干燥形成。气溶胶最初的小尺寸允许 有效的深肺输送，即使是在患病的肺部，并且包含 MN 作为吸湿性赋形剂 导致肺部内气溶胶尺寸增加和有针对性的沉积。一种简单的活性干粉吸入器 将开发采用新的三维（3D）棒阵列技术的（DPI）系统，该技术具有 先前已被证明可以在儿科所需的低流量下有效地解聚无载体粉末 应用程序。初始粒径和吸湿性赋形剂含量将被设计为产生受控的 气溶胶尺寸增加和沉积，从而在气道中提供均匀浓度的妥布霉素 表面液体。为了开发这种新方法，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促进生长 (TOB-EEG) 制剂，该制剂 与内联干粉吸入器 (DPI) 系统结合使用时，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) 和体外方法来开发和 为不同年龄段的儿科 CF 患者优化高效、高剂量的主动 DPI 系统。 具体目标 3：预测并优化妥布霉素在肺气道中的局部肺部输送浓度 使用CFD表面液体，并评估妥布霉素和赋形剂浓度对体外的影响 痰液渗透性和抗菌活性。 这种新提出的 TOB-EEG 吸入疗法将允许在 6 岁以下的儿科患者中有效使用 DPI 第一次老。开发便捷的 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。新开发的TOB-EEG 配方将显着增加气溶胶输送到小气道，提供更多 使抗生素浓度均匀分布在气道内，提高抗生素的渗透性 通过粘液提高细菌的消灭能力。

项目成果

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。

• 发表时间: 2022-01
• 影响因子: 4.5
• 作者: Thomas, Morgan L;Longest, P Worth
• 通讯作者: Longest, P Worth

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

含有粘液惰性颗粒的干粉气雾剂，用于赋形剂增强肺部药物输送的生长。

• 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

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

肺部疾病中的气道粘液：粘膜粘附和粘膜穿透颗粒可克服气道粘液屏障。

• DOI: 10.1016/j.ijpharm.2023.122661
• 发表时间: 2023-02-01
• 期刊: International journal of pharmaceutics
• 作者: R. Pangeni;Tuo Meng;Sagun Poudel;Divya Sharma;Hallie Hutsell;Jonathan Ma;B. Rubin;Worth Longest;M. Hindle;Qingguo Xu
• 通讯作者: Qingguo Xu

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

使用二方程湍流模型模拟类似于上呼吸道条件下的微粒沉积的建议。

• 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