Biorelevant and flexible dose deposition of drug substance powders and nebulised liquids onto filters and cell-cultures

Frans Franek¹, Gabriella Yousef¹, Kinga Balogh Sivars², Helena Thörn¹, Rebecca Fransson³ & Ulrika Tehler³

AstraZeneca R&D, Pepparedsleden 1, Mölndal, 43183, Sweden

¹Pharmaceutical Technology & Development Inhalation, Operations

²Safety & ADME Translational Sciences, IMED

³Pharmaceutical Sciences, IMED

Summary

Deposition of various inhaled powders and nebulised liquids onto different surfaces may facilitate investigations of API and/or drug product dissolution, absorption, toxicity and efficacy. Three in vitro dose deposition systems are presented. Inhaled active pharmaceutical ingredients (APIs) were administered onto filters or cell cultures, as pure powders, formulations, nebulized solutions or suspensions using a modified Anderson Cascade Impactor (mACI), a mesh nebulizer and a jet nebulizer, respectively. An API powder dose range between 0.3 ng – 40 µg/cm² can be achieved since only 0.03-0.2% of the powder reaches a 12 mm diameter filter/cell surface. Similarly, for nebulized liquids, the API dose can be altered by changing concentration or nebulised volume. Powder and nebulised dosing was reproducible (21 and 10 % RSD, respectively) and provides the potential to investigate what can be regarded as biorelevant lung doses (0.4-200 ng/cm²). In addition to investigating mACI dose deposition, the dissolution and absorption of fluticasone furoate was examined.  The dissolution in the Transwell setup was shown to be much faster than the absorption across both Caco-2 and a primary air liquid interface bronchial cell cultures. The mACI was also examined for its feasibility to provide a methodology for toxicological evaluation of various formulations. Powder and nebulised solution of a known toxic API were deposited and induced a significant decrease in transepithelial electrical resistance compared to the control. The presented methods can deposit low and flexible doses of powders and nebulized liquids, which provides valuable in vitro dose deposition systems for investigations of API and/or drug product dissolution, absorption, toxicity and efficacy.