In silico investigation of the effect of particle diameter on deposition uniformity in pulmonary drug delivery

摘要

Systemic drug delivery via the pulmonary route has a critical limitation because dose uniformity is strongly dependent upon patient inhalation technique. The most frequent and critical errors in inhalation technique are overly forceful inspiration and insufficient breath-holding. In this study, response surface methodology was used with an in silico whole lung particle deposition model for bolus administration to investigate whether varying the inhaled drug particle size could reduce the dependence of deposition upon flow rate and/or breath-holding duration. The range of particle aerodynamic diameters studied was 0.1-10 mu m for flow rates between 500-2000 mL/s and breath-holding duration between 0-15 seconds. Comparison with published experimental data showed that this modeling approach can accurately predict the lung deposition. The simulation results indicated that the deposition of particles with aerodynamic diameter in the range of 0.1-1.5 mu m should be minimally affected by flow rate over the 500-2000 mL/s range. There was found to be no particle size whose deposition was completely independent of breath-holding duration. The smallest particles, whose deposition is diffusion-driven, were found to be the least sensitive to breath-holding time, but this size is of limited practical use. On the other hand, the simulations indicated that particles with a 1.5 mu m diameter would provide acceptable consistency in dose reaching the acini region when the breath-holding duration was greater than 10 seconds. It is hoped that this finding could provide a means of improving dose uniformity for systemic delivery via the pulmonary route by facilitating simplified patient instructions.