Novel Inhalable Formulations for Targeted Delivery of Antibiotics to the Lung:
A Response to the Global Tuberculosis Commitment
Sharareh Salar-Behazdi1,2, Carolina Corzo1, Eleonore Fröhlich1,3, Dirk Lochmann4, Sebastian Reyer4, Andreas Zimmer2
1Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010, Graz, Austria
2Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmaceutics, University of Graz, Universitätsplatz 3, 8010, Graz, Austria
3Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, 8010, Graz, Austria
4IOI OLEO GmbH, Arthur-Imhausen-Straße 92, 58453, Witten, Germany
Summary
This work is a response to the significant increasing demand on the inhalable antibiotic drugs for efficient localized delivery to the lung. We aimed to engineer safe and novel lipid-microparticles loaded with rifampicin via spray-drying, to be administered as a carrier-free dry powder for inhalation.
Despite the well-known strong technical limitations of spray-drying of lipids, a completely lipid-based formulation was successfully developed, using diglycerol full ester of behenic acid and glyceryl stearate citrate as emulsifier.
Exceptional thermal and solid-state properties of lipid as a homogeneous system with high melting temperature, low super-cooling (ΔT=Tm-Tc) and absence of polymorphism were the key factors to avoid softening of material during spray drying and to gain a high yield of 83%. The achieved mass median aerodynamic diameter and median geometric size of particles were 2.36 µm and 2.05 µm, respectively. Those properties together with the negative surface (-50.03 mV) of particles were defined as critical factors for deposition in the deep lung and targeted delivery of rifampicin to alveolar macrophages. The fine particle fraction was 79.5%. The in vitro uptake of particles into THP-1 macrophages was confirmed by fluorescence imaging and by determination of the rifampicin content inside the alveolar macrophages. The in vitro safety of particles was confirmed based on cytotoxicity studies on alveolar and bronchial epithelial cells ((A549 and Calu-3 cell lines, respectively), as well as on alveolar macrophages (THP-1 cells).
This study paves the way to extend the use of lipid-based formulations for advanced targeted delivery to the lung.