In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.     

Application of a new dosimetry program TAOCS to assess transient vapour absorption in the upper airways

Most previous models of vapour absorption in the respiratory tract have assumed steady state flow fields and steady state diffusion into the airway walls. However, recent studies have shown that transient absorption flux into the walls of the upper airways can significantly influence predicted uptake or deposition values. The disadvantage of accounting for transient absorption into the airway walls is a more complex boundary condition and numerical model. The objective of this study was to evaluate the effects of both transient flow fields and transient mass absorption on the uptake of highly and moderately soluble compounds in an upper airway model. The geometry consisted of the mouth-throat region coupled with a multilayer wall model containing air, mucus, tissue, and blood phases. Based on previous studies, a boundary condition that represents transient absorption into the airway walls was applied. A new dosimetry program, named transient absorption of chemical species (TAOCS) 1.0, was developed and implemented to determine the coefficients needed for the transient boundary condition expression and to apply the boundary condition to the computational fluid dynamics (CFD) model. Both steady state and transient conditions were considered for the airflow field and wall absorption. The case of perfect wall absorption with a zero surface concentration was also considered. Results indicated that steady state airflow provided a reasonable approximation to transient airflow conditions in terms of total and local deposition (values within 10-30%). However, the simulation of transient wall absorption was critical unless the compound was highly soluble (with a mucus-air partition coefficient ≥320), in which case a perfect absorption boundary condition was accurate to within a relative difference of 50%. Still, the perfect absorption boundary condition did not accurately capture local deposition enhancement factor values. Based on these findings, implementation of the transient absorption boundary condition appears critical to predict local deposition characteristics for even highly soluble compounds. Use of the TAOCS program simplified the implementation of the complex transient absorption condition making the CFD simulation process more efficient and user-friendly.     

The Use of Condensational Growth Methods for Efficient Drug Delivery to the Lungs during Noninvasive Ventilation High Flow Therapy

Purpose

The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques.

Methods

An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations.

Results

Significant improvement in the lung dose (3–4× increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5 μm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results.

Conclusions

These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally-administered drugs to the lungs.     

Aerodynamic Factors Responsible for the Deaggregation of Carrier-Free Drug Powders to Form Micrometer and Submicrometer Aerosols

Purpose

To employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform.

Methods

Eight airflow passages were evaluated for deaggregation of the aerosol including a standard constricted tube, impaction surface, 2D mesh, inward radial jets, and newly proposed 3D grids and rod arrays. CFD simulations were implemented to evaluate existing and new aerodynamic factors for deaggregation and in vitro experiments were used to evaluate performance of each inhaler.

Results

For the carrier-free formulation considered, turbulence was determined to be the primary deaggregation mechanism. A strong quantitative correlation was established between the mass median diameter (MMD) and newly proposed non-dimensional specific dissipation (NDSD) factor, which accounts for turbulent energy, inverse of the turbulent length scale, and exposure time. A 3D rod array design with unidirectional elements maximized NDSD and produced the best deaggregation with MMD<1 μm.

Conclusions

The new NDSD parameter can be used to develop highly effective dry powder inhalers like the 3D rod array that can efficiently produce submicrometer aerosols for next-generation respiratory drug delivery applications.