Preclinical safety evaluation of intravenously administered mixed micelles

Mixed micelles, with their main constituents lecithin and glycocholic acid, form a new principle for the parenteral administration of compounds which are poorly water-soluble. Their composition of mainly physiological substances as well as their comparatively good stability substantiate their attractivity in comparison to existing solvents. A decomposition due to physical influences such as heat or storage for several years will almost exclusively affect the lecithin component in the form of hydrolysis into free fatty acids and lysolecithin. Their toxicity was examined experimentally in various studies using both undecomposed and artificially decomposed mixed micelles. In these studies the mixed micelles were locally and systemically well tolerated and proved to be neither embryotoxic, teratogenic nor mutagenic. Only when comparatively high doses of the undecomposed mixed micelles were administered, corresponding to approximately 30 to 50 times the anticipated clinical injection volume (of e.g. diazepam mixed micelles), did some vomitus (dogs), slight liver enzyme elevation (rats and dogs), and slightly increased liver weights (dogs) occur. After repeated injections of the artificially decomposed formulation (approximately 25% of lecithin hydrolyzed to free fatty acids and lysolecithin) effects such as intravascular haemolysis, liver enzyme elevations and intrahepatic cholestasis (dogs only) were observed but only when doses exceeding a threshold of approximately 40 to 60 mg lysolecithin/kg body weight were administered. All alterations were reversible after cessation of treatment.