Amphotericin B Formulated in Liposomes and Lipid Based Systems: A Review

Abstract

The therapeutic index (T.I.) of amphotericin B (amB) is significantly increased when the drug is formulated in a variety of liposome and lipidic systems. This increase is due to a dramatic decrease in toxicity with maintenance of antifungal activity. Three formulations are currently being commercialized: ABLC™, AmBisome and Amphocil™. ABLC™ is a ribbon-type lipid complex with a diameter in the 2-5 micron range consisting of dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol and amB (7/3/10 mole ratio). AmBisome™ is a liposome with a particle diameter less than 100 nm and composed of hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol and amB (2/1/0.8/0.4 mole ratio). Amphocil™ is a lipidic particle with a diameter of 115 nm and consists of cholesterylsulfate and amB (1/1 mole ratio). In spite of the differences, each formulation reduces the transfer of amB into a sensitive site of toxicity while affecting transfer of the drug into the fungal target to a lesser extent. Two principal mechanisms account for this: vehicle composition decreases the transfer rate of amB into cholesterol containing mammalian membranes (sites of toxicity) more than into ergosterol containing fungal membranes (sites of efficacy). Vehicle diameter influences the pharmacokinetics and disposition of the drug into the reticuloendothelial system. Immediate toxicity is reduced because the drug is rapidly eliminated from the central compartment and directed into macrophages. Subsequent release from macrophages at sites of infection can improve die efficacy. The chapters in this volume review the current understanding of the mechanism of amB and cover in detail die biophysical, pharmaceutical and therapeutic aspects of amphotericin B lipid formulations.