S Radivojev1,2, M Beretta1,3, V Reinisch1, V Rehbein1, J T Pinto1, E Frönlich1,2, & A Paudel1,3
1Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz, 8010, Austria
2Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, Graz, 8010, Austria
3Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, Graz, 8010, Austria
Summary
Dry powder inhalers (DPIs) are commonly used systems for the delivery of inhaled therapeutics. Most of the available DPI systems consist of larger carrier excipient particles (in the size range of 100-150 µm) mixed with the micronized drug (typically 1-5 µm), resulting in a complex interplay between (i) selecting proper blending parameters (ii) identifying the optimal carrier particle properties, as well as (iii) selecting the most appropriate device for delivery. Therefore, the aim of this study was to evaluate the blending parameters necessary to produce homogeneous blends of a Budesonide (BUD)/Formoterol Fumarate (FF) DPI. For this, a resonant acoustic mixer was used and short blending times (30 and 90 s) combined with different acceleration levels (30, 45 and 60 g) were applied. Two different carriers were used (α‑lactose monohydrate (αLH) and mannitol (MAN)), while the aerosolization performance was investigated using two types of inhalers, namely Cyclohaler® (CH) and Novolizer® (NOV). Finally, the predicted deposition patterns were evaluated. We found that for αLH blends, homogeneity was achieved with lower blending times compared to MAN containing ones. Nevertheless, the selection of MAN as a carrier in a combination with NOV resulted in the improvement of the aerodynamic performance of the BUD/FF combination therapy. In-silico modelling of the deposition profiles showed that different formulation strategies, resulted in comparable fractions of the delivered to the peripheral (P) and central (C) region of the lung yet different in the extra-thoracic region (ET). This could be relevant when designing formulations intended for a localized therapeutic effect.
Key Message
Investigation of the process parameters and carrier types showed that MAN combined with reservoir type of device could deliver higher amounts of drugs to the lungs. The developed deposition model showed the relevance of investigating further subtle differences present in aerodynamic performance data when developing a DPI formulation.