Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zellnitz, L.
Influence of different drug shapes on biological effects in the lung
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2018. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Fröhlich Eleonore
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- Abstract:
- For administering active pharmaceutical ingredients (APIs) to the lung, a particle size of 1-5 µm is needed. The most common technique to generate small, inhalable sized particles is milling of the API, but spray drying has shown to be a suitable alternative. Both techniques lead to inhalable sized particles but the shape of the particles and other properties, e.g. solid-state, can vary. The model drug chosen for this study is salbutamol sulphate (SS). It is a short acting beta-2 agonist and a frequently used drug in the treatment of bronchial asthma and COPD (chronic obstructive pulmonary disease). Previous studies showed that spray drying of SS creates spherically shaped, amorphous particles, whereas milling normally keeps the needle-like shape of the drug crystals. The aim of this work was to identify whether the particle shape has an influence on the biological effects of the inhalable particles in the lung. Permeability experiments and cellular uptake experiments were performed, using distinct cell lines: Calu-3 cells were used for permeability testing and DMBM-2 cells, which represent alveolar macrophages, were used for cellular uptake experiments. A549 cells, which represent a well-established model for type-I-alveolar cells, were used for both experimental set ups. Inhalable formulations were prepared with jet-milled and spray dried SS particles and Lactohale 100 (LH100) as a model carrier. The different formulations were used for determining the dissolution behaviour of the particles, as well as the in-vitro respirable fraction, which was tested with a next generation impactor (NGI). Jet-milled particles resulted in higher respirable fractions, compared to spray dried particles. This has already been shown in previous studies. Regarding the cellular experiments, lower apparent permeability coefficient values (Papp-values) and lower uptake in macrophages could be shown for jet-milled particles. Spray dried, spherically shaped particles, showed higher epithelial permeability and higher uptake by macrophages. However, both formulations showed similar dissolution behaviour and dissolution was almost complete after 2 minutes. This fact makes a prominent influence of phagocytosis rather unlikely and leads to the suggestion that distinct uptake-mechanisms must occur. It is possible that, after partial dissolution, the crystalline particles were in the range for preferential active uptake by epithelial cells. For future experiments, an API with lower solubility will be chosen in order to get detailed insight on the impact of particle shape.