Numerical study on the effect of the realistic mouth-inhaler positions on orally inhaled drug delivery in pediatric intersubject upper airways

The relative position between the pediatric upper airway and the inhalation device during real inhalation administration has significant effects on the delivery efficiency of orally inhaled drugs. Morphological variability plays an important role in this process. However, the mouth-throat differences between adults and children were usually neglected because most of the commercial inhalation devices currently are designed for adults or older adolescents. The main objective of this study is to investigate these effects by four realistic pediatric mouth-throat (RMT) geometries. In addition, an idealized mouth-throat (IMT) model was developed to validate the numerical model and to compare with the RMT models. Computational fluid dynamics (CFD) simulations were performed to investigate the flow pattern and deposition pattern in these models and the results were compared with the cascade impactor experiments, replica experiments and in vivo results. No significant correlation (p > 0.1) between the relative position parameters and inhaler insertion depth can be noticed among the RMT models. Notably, significant variability in the inhaler posture was observed in RMT models, especially for the S4 model. Airflow structure shows that the RMT model has a complex onset of turbulence, reverse flow and subsequently vortex formation when compared with the IMT model. The oral cavity is the region with the largest deposition fraction (DF) and deposition efficiency (DE). The DF and DE of the oral cavity are negatively correlated to the position parameter (L_m) when mass median aerodynamic diameter (MMAD) of indacaterol 150 μg was utilized as the input particle parameter. The relative position between the inhaler and oral cavity has significant effects on the particle transport and deposition. Furthermore, in silico results overestimated the lung deposition in comparison to the in vivo and experimental results when MMAD was used as input. To resolve the disparity between the in silico and in vivo results, a modified prediction method based on the cascade impactor and original in silico results was proposed and a good correlation of the relative contribution of pulmonary absorption to total systemic exposure (f_lung) was found between the predicted and observed results. The findings of present work will provide useful information in understanding the particle transport and deposition in the pediatric airways for the design of inhaler.