CFD assessment of respiratory drug delivery efficiency in adults and improvements using controlled condensational growth.

摘要

Pharmaceutical aerosols provide a number of advantages for treating respiratory diseases that include targeting high doses directly to the lungs and reducing exposure of other organs to the medication, which improve effectiveness and minimize side effects. However, difficulties associated with aerosolized drug delivery to the lungs include drug losses in delivery devices and in the extrathoracic region of human upper airways. Intersubject variability of extrathoracic and thoracic drug deposition is a key issue as well and should be minimized. Improvements to respiratory drug delivery efficiency have been recently proposed by Dr. P. Worth Longest and Dr. Michael Hindle through the use controlled condensational growth methods, which include enhanced condensational growth (ECG) and excipient enhanced growth (EEG). These methods reduce inhaled drug loss through the introduction of an aerosol with an initial submicrometer aerodynamic diameter, which then experiences condensational growth to increase droplet size and enhance thoracic deposition. Tracheobronchial and nasal human airway computational models were developed for this study to assess drug delivery using conventional and EEG methods. Computational versions of these models are used to assess drug delivery and variability with computational fluid dynamics (CFD) simulations, which are validated with experimental data where possible. Using CFD, steady state delivery of albuterol sulfate (AS) during high flow therapy (HFT) through a nasal cannula was characterized with four nasal models developed for this study, with results indicating an increase in average delivered dose from 24.0% with a conventional method to 82.2% with the EEG technique and an initially sized 0.9 microm aerosol, with a corresponding decrease in the coefficient of variation from 15% to 3%. Transient CFD simulations of nebulized AS administration through a mask during noninvasive positive pressure ventilation (NPPV) were performed and validated with experimental data, which resulted in 40.5% delivered dose with the EEG method as compared with 19.5% for a conventional method and a common inhalation profile. Using two newly created face-nose-mouth-throat models, dry powder delivery of ciprofloxacin during NPPV was assessed for the first time with steady state CFD predictions, which showed an increase in average delivered lung dose through a new mask design of 78.2% for the EEG method as compared with 36.2% for conventional delivery, while corresponding differences in delivered dose between the two models were reduced from 45.4% to 12.8% with EEG. In conclusion, results of this study demonstrate (i) the use of highly realistic in silico and in vitro models to predict the lung delivery of inhaled pharmaceutical aerosols, (ii) indicate that the EEG approach can reduce variability in nose-to-lung aerosol delivery through a nasal cannula by a factor of five, and (iii) introduce new high efficiency methods for administering aerosols during NPPV, which represents an area of current clinical need.