Sneha Dhapare1, Abhinav Mohan1, Bryan Newman1; Mårten Svensson2; Peter Elfman2; Dennis Sandell3,#, Larry Winner 4, Simon Berger5, Jürgen Bulitta5, Günther Hochhaus5
1 Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
2 Emmace Consulting AB, Scheelevägen 22, SE-223 63 Lund, Sweden
3 S5 Consulting, Ekvägen 8, SE-275 62 Blentarp, Sweden; # In Memoriam, October 29, 2020
4 Department of Statistics, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL, USA
5 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
Summary
The size of droplets and particles emitted by a metered dose inhaler (MDI), and passing through the mouth-throat (MT) region play a key role in determining lung deposition. Realistic in vitro studies that measure the amount and size distribution of aerosols exiting an anatomical MT model are expected to improve predictability of in vivo lung deposition. In this paper, we present a systematic analysis of the effects of five different in vitro test factors (MT models, inhalation profiles (IP), MT model coatings, MDI insertion angles (IA) into the MT models and MDI firing point (FP)) on the aerodynamic particle size distribution (APSD) and droplet size distribution (DSD) of three commercial MDIs using the cascade impactor and laser diffraction (LD) methods, respectively. The goal of this research was to investigate the effects of these factors on the particle size distribution of two model suspension MDIs, Flovent® HFA (fluticasone propionate, 0.22 MG/INH) and Symbicort® (budesonide, 0.16 MG/INH; formoterol fumarate, 0.0045 MG/INH) and a model solution MDI, Atrovent® HFA (ipratropium bromide, 0.021 MG/INH). MT geometries appeared to have the strongest effects on the APSD-derived parameters, while the effects of IP depended on the product type. In comparing the cascade impaction and LD methods, limited correlations were observed between MMAD, fine particle fraction < 5 μm, fine particle dose < 5 μm and Dv50, which were dependent on the type of product and the active ingredient.
Key Message
The MT geometry had the strongest effect on the APSD-derived parameter of the investigated suspension and solution based commercial MDIs. Overall, the effects of the investigated factors on the DSD were often product-specific and unrelated to the formulation type (i.e., suspension or solution).