The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) loaded with sildenafil. The SLNs were tested as a new drug delivery system (DDS) for the inhalable treatment of pulmonary hypertension in human lungs. Solubility of sildenafil in SLN lipid matrix (30:70 phospholipid:triglyceride) was determined to 1% sildenafil base and 0.1% sildenafil citrate, respectively. Sildenafil-loaded SLN with particle size of approximately 180 nm and monomodal particle size distribution were successfully manufactured using a novel microchannel homogenization method and were stable up to three months. Sildenafil-loaded SLN were then used in in vitro and ex vivo models representing lung and heart tissue. For in vitro models, human alveolar epithelial cell line (A459) and mouse heart endothelium cell line (MHEC5-T) were used. For ex vivo models, rat precision cut lung slices (PCLS) and rat heart slices (PCHS) were used. All the models were treated with plain SLN and sildenafil-loaded SLN in a concentration range of 0-5000 µg/ml of lipid matrix. The toxicity was evaluated in vitro and ex vivo by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Median lethal dose 50% (LD50) values for A549 cells and PCLS were found to be in the range of 1200-1900 µg/ml while for MHEC5-T cells and precision cut heart slices values were found between 1500 and 2800 µg/ml. PCHS showed slightly higher LD50 values in comparison to PCLS. Considering the toxicological aspects, sildenafil-loaded SLN could have potential in the treatment of pulmonary hypertension via inhalation route.
Experimental investigations of the effect of microchannel geometry on high-pressure dispersion and emulsification were carried out. Customized microchannels of varying geometric principles were fabricated in silicon and steel. In order to characterize the process efficiency of microchannel geometries, the effects of the process parameters (mean velocity, Reynolds number, and local pressure drop) were examined and correlated to the dispersion and emulsification results. It is demonstrated that high pressure losses focused at a small channel length and high velocity gradients lead to high stress intensities and, in consequence, to low particle or droplet sizes. Thus, 2D orifices were successfully further improved regarding their process efficiency by adding a third-dimension constriction.
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