Understanding Carrier Performance in Low-Dose Dry Powder Inhalation: An In Vitro–In Silico Approach

The use of physiologically based pharmacokinetic (PBPK) models to support drug product development has become increasingly popular. The in vitro characterization of the materials of the formulation provides valuable descriptors for the in silico prediction of the drug’s pharmacokinetic profile. Thus, the application of an in vitro–in silico framework can be decisive towards the prediction of the in vivo performance of a new medicine. By applying such an approach, this work aimed to derive mechanistic based insights into the potential impact of carrier particles and powder bulk properties on the in vivo performance of a lactose-based dry powder inhaler (DPI). For this, a PBPK model was developed using salbutamol sulphate (SS) as a model drug and the in vitro performance of its low-dose blends (2% w/w) with different types of lactose particles was investigated using different DPI types (capsule versus reservoir) at distinct airflows. Likewise, the influence of various carrier’s particle and bulk properties, device type and airflow were investigated in silico. Results showed that for the capsule-based device, low-dose blends of SS had a better performance, when smaller carrier particles (Dv_0.5 ≈ 50 μm) with about 10% of fines were used. This resulted in a better predicted bioavailability of the drug for all the tested airflows. For the reservoir type DPI, the mean particle size (Dv_0.5) was identified as the critical parameter impacting performance. Shear cell and air permeability or compressibility measurements, particle size distribution by pressure titration and the tensile strength of the selected lactose carrier powders were found useful to generate descriptors that could anticipate the potential in vivo performance of the tested DPI blends.

Download the full publication here: Understanding Carrier Performance in Low-Dose Dry Powder Inhalation- An In Vitro–In Silico Approach

or continue reading here: Pinto, J.T.; Cachola, I.; F. Pinto, J.; Paudel, A. Understanding Carrier Performance in Low-Dose Dry Powder Inhalation: An In Vitro–In Silico Approach. Pharmaceutics 2021, 13, 297. https://doi.org/10.3390/pharmaceutics13030297

Materials Micronized salbutamol sulphate (racemic mixture, Fagron GmbH & Co., Glinde, Germany) with a particle size of Dv0.1 = 0.43 ± 0.01 μm, Dv0.5 = 1.53 ± 0.07 μm and Dv0.9 = 3.79 ± 0.26 μm was chosen as a model API. In line with our previous work [1], Duralac© H (16% α anomer and 83.5% β anomer, Meggle, Wasserburg am Inn, Germany), α-lactose monohydrate Flowlac© 90 (β anomer ≤3%, Meggle, Wasserburg am Inn, Germany), Respitose© SV003 (β anomer ≤ 3%, DFE pharma, Goch, Germany) and Lactohale© 100 (β anomer ≤3%, DFE pharma, Goch, Germany), were used as model carriers. Flowlac® 90 was dry sieved using a vibratory sieve shaker (Retsch AS200, Germany) to obtain its 20–90 μm particle size fraction. Purified water (TKA Wasseraufbereitunssystem GmbH, Niederelbert, Germany) and acetic acid (Emprove, Merck Millipore, Burlighton, MA, USA) were used to dissolve SS.