title: PEGylated bile acids for use in drug delivery systems: enhanced solubility and bioavailability of itraconazole.
abstract: 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.
authors.affiliation: Department of Chemistry, Université de Montréal , CP 6128 Succursale Centre-ville, Montréal, QC, H3C 3J7, Canada.
authors.forename: Frantz
authors.initials: F
authors.lastname: Le Dévédec
authors.forename: Satu
authors.initials: S
authors.lastname: Strandman
authors.forename: Patrice
authors.initials: P
authors.lastname: Hildgen
authors.forename: Grégoire
authors.initials: G
authors.lastname: Leclair
authors.forename: X X
authors.initials: XX
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D001682:Biological Availability; D018938:Caco-2 Cells; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D001647:Bile Acids and Salts; D017964:Itraconazole; D011092:Polyethylene Glycols