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.
Treatment of 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. 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 with the advantages of rapid administration, high efficiency lung delivery, uniform antibiotic concentration in the airways, and improved penetration through mucus. Compared with existing treatment, expected therapeutic advantages include use of a dry powder inhaler for early eradication of infections in patients as young as 2 years old and more efficient treatment of chronic infections with the potential for eradication.
| Bass, Karl; Longest, P Worth (2018) Development of an infant complete-airway in vitro model for evaluating aerosol deposition. Med Eng Phys : |
| Bass, Karl; Longest, P Worth (2018) Recommendations for Simulating Microparticle Deposition at Conditions Similar to the Upper Airways with Two-Equation Turbulence Models. J Aerosol Sci 119:31-50 |
