PEGylated Bile Acids for Use in Drug Delivery Systems: Enhanced Solubility and Bioavailability of Itraconazole

Itraconazole is a drug of choice for the treatment of severe fungal infections and parasitic diseases, but its use is limited by its low water solubility and varying bioavailability. New self-emulsifying drug delivery systems (SEDDS) based on PEGylated bile acids (BA-PEGs) were designed and prepared, where the number and length of PEG arms were varied to optimize the loading of itraconazole in the final drug formulation. The use of both BA-PEGs and oleic acid improved the solubilization and absorption of the drug, which was in a glassy state in the SEDDS prepared with the melting method. High loading efficiencies of itraconazole (up to 20%) and stable liquid formulations were obtained at neutral pH, and full dispersion of itraconazole was reached in 2 h in simulated intestinal fluid (pH 6.8). Aqueous emulsions consisting of spherical micelles with mean hydrodynamic diameters (Dh) of ca. 75-220 nm, as verified by transmission electron microscopy and dynamic light scattering, are expected to improve the intestinal absorption of the drug. The new SEDDS showed good cytocompatibility by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays of BA-PEGs with Caco-2 and RAW 264.2 cells, and a low degree of hemolysis of human erythrocytes. The SEDDS based on PEGylated bile acids provide a controlled release system with significant improvement of the bioavailability of itraconazole in rats, as demonstrated by the pharmacokinetic studies.