Cytotoxicity screening of emulsifiers for pulmonary application of lipid nanoparticles.

ABSTRACT

INTRODUCTION: The pulmonary route is a non-invasive administration route that receives growing attention. The challenge for formulation development of orally inhaled formulations is, however, the limited number of approved excipients. Lipid nanoparticles are desired drug delivery systems for inhalation because lipids are biocompatible. However, addition of emulsifiers to stabilize the formulation may cause toxic effects. Alveolar epithelial cells and alveolar macrophages are the main cell types that get in contact with inhaled formulations in the deep lung. The different cell types are supposed to differ in the extent of particle uptake. Kolliphor RH40, Poloxamer 188, and Tween 80 are approved for use in oral formulations and widely used in the academic field for manufacturing of lipid nanoparticles. However, little is known about their pulmonary toxicity. METHODS: Cytotoxicity of Kolliphor RH40, Poloxamer 188, and Tween 80 was studied by integration into solid lipid nanoparticles loaded with itraconazole as model drug. Cytotoxicity of the formulations was assessed in human alveolar epithelial cells and human and murine macrophages and correlated to cell uptake. RESULTS: The tested emulsifiers showed overall low cytotoxicity with less pronounced adverse effects in human cells than in murine macrophages. Cellular uptake of Poloxamer 188 containing lipid nanoparticles was decreased in macrophages, while uptake of lipid nanoparticles with the other emulsifiers was similar in epithelial cells and phagocytes. CONCLUSION: The tested emulsifiers appear suitable for use in pulmonary applications. Due to larger cell size and lower proliferation rate human cells showed lower cytotoxicity than the murine cells. Being human cells, they appear more suitable for the screening of adverse effects in human lungs.