Same lung deposited dose in dog dosing a fine and coarse aerosol indicates no difference in intranasal filtration

Abstract

A novel inhalation exposure system was developed with the aim to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog. It enables collecting PK data for multiple drug candidates in a single experiment by simultaneous administration of the drugs to the same animal. This facilitates a direct PK comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective. The system design was inspired by a clinical precision dosing dosimeter systems, which enhance dosing precision by synchronizing the aerosol delivery from the jet nebulizer with the inhalation to maximize the inhaled fraction of the nebulized dose.The performance of the novel system was validated in an in-vivo study, which included a comparison of the same nebulized dose delivered as a fine and a coarse aerosol. The drugs selected for this study were developed for local treatment of the lung via inhalation and were known to have low oral bioavailability due to being extremely poorly soluble and therefore expected to also have low nasal bioavailability. This would result in systemic exposure derived primarily from pulmonary absorption, which facilitated the PK assessment applied to determine the lung deposited dose.The jet nebulizer selected to generate a fine aerosol was designed for alveolar lung deposition and approved by U.S. Food and Drug Administration for lung ventilation imaging, and the nebulizer selected to generate a coarse aerosol was a standard nebulizer. The drugs were wet milled to a particle size considerably smaller than the nebulized droplets and the dispersed drug particles were therefore homogenously distributed in the droplet size distribution.Higher initial plasma concentrations were observed for the fine aerosol. This was expected, as the smaller droplets should deposit more efficiently in the peripheral regions of the lung, which consequently should lead to a faster absorption compared with the coarse aerosol from the standard nebulizer that should deposit more centrally. The fact that this could be observed supports that the novel system is an excellent tool in PK evaluations.Our study indicated that there was no difference in the systemic exposure between the fine and the coarse aerosol for the same nebulized dose, and thus the lung deposition was also the same. The considerable difference in the nebulized size distribution within the range relevant for available inhalation devices resulted in a negligible difference in intranasal filtration. The fraction of the nebulized dose that deposited in the lung was observed to be high in this study (mean of 21–30% and about 50% for one dog with a distinguished slow and deep breathing), which supports that the intranasal filtration was low. That a high fraction of the nebulized dose deposited in the lung indicates that an enhanced dosing precision was obtained with the novel system. The similar achieved lung doses of all three drugs, shows that the simultaneous administration of multiple drugs worked well.That the intranasal filtration was low is an important finding considering that devices for oropharyngeal delivery in dogs are applied in order to eliminate intranasal filtration. Oropharyngeal dosing is more invasive compared with oronasal dosing and avoiding utilizing that method can be considered a refinement measure from an animal research perspective.