(621f) Preparation of Adhesive Mixtures of Surface Modified Glass Beads As Model Carriers in Dry Powder Inhalers and Spray Dried Salbutamol Sulphate

In order to use API (active pharmaceutical ingredient) drug particles intended to target the tiny airways of the deep lung in dry powder inhalers (DPIs), they must have an aerodynamic diameter of 1 µm  - 5 µm. Particles of this size are rather cohesive and possess poor flow properties [1], which lead to difficulties concerning volumetrically dosing. To overcome this problem, carrier based formulations, where the API is attached to the surface of a larger carrier particle (50 µm – 200 µm) of adequate flowability were developed. Interparticle interactions play a key role in this kind of formulations. On the one hand they have to be high enough that uniform dosing is possible and on the other hand low enough that drug detachment from the carrier surface during inhalation is guaranteed.

As the surface topography of the carrier largely affects interparticle interactions [2], the model carriers used in this work are surface modified glass beads. By physical surface modification in a ball mill glass beads with different shades of roughness have been generated using quartz and tungsten carbide powders [3]. The focus of the present work lies on the preparation of adhesive mixtures of these surface modified glass beads and a model API.

Spray dried salbutamol sulphate was chosen as model API and prepared on a Nano Spray Dryer B-90. It shows the characteristic diameters of x₁₀=0.45 µm, x₅₀=3.07 µm and x₉₀=6.73 µm. Glass Beads in the size range of 400 µm to 600 µm (x₅₀=537.3 µm) processed with quartz (x₅₀=32 µm ) for 4 hours and tungsten carbide (x₅₀=25 µm) for 8 hours were used. Adhesive mixtures, with 100% calculated surface coverage of API, were prepared in a tumble blender.  

First the homogeneity of the mixtures (expressed as the coefficient of variation of the drug content of n=10 samples out of the mixture and analyzed via high pressure liquid chromatography (HPLC)) was determined and the actual coverage, based on the HPLC results, was calculated. Additionally in vitro lung deposition experiments were performed with a next generation impactor (NGI) and the fine particle fraction (FPF), which is supposed to correlate wit the respirable fraction in vivo, was calculated.

The results show that regardless of what glass beads were used a 100% surface coverage could not be achieved although the amount of API weighed in was calculated for a 100% surface coverage. The actual surface coverage reached for the physically modified glass beads was about 75% compared to a 32% actual surface coverage for the untreated glass beads. By preparing adhesive mixtures with different calculated surface coverage, the calculated coverage and the actual coverage could be correlated for the all the distinct glass beads used and linear equations with different slopes could be set.

Moreover the evaluation of the FPFs shows that the FPF depends on the surface modification, but is independent of the surface coverage.

The obtained data are highly useful to improve the understanding of the mixing behavior of surface modified glass beads, and will help to generate adhesive mixtures whose FPFs and performances can be compared among each other.

Acknowledgements

The authors wish to thank the DFG for financial support within the priority program SPP 1486 “Particles in contact”

References

[1]       D.I. Daniher, J. Zhu, Dry powder platform for pulmonary drug delivery, Particuology. 6 (2008) 225–238.

[2]       M. Lohrmann, Adhaesionskräfte in interaktiven Mischungen fuer Pulverinhalatoren, PhD thesis University Duesseldorf, 2005.

[3]       S. Zellnitz, J.D. Redlinger-Pohn, M. Kappl, H. Schroettner, N.A. Urbanetz, Preparation and characterization of physically modified glass beads used as model carriers in dry powder inhalers., International Journal of Pharmaceutics. 447 (2013) 132–8.