Amphotericin B Formulations – The Possibility of Generic Competition

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…Amphotericin B, a macrolide polyene antibiotic produced by Streptomyces nodosus, has been considered the gold standard drug for the treatment of severe systemic fungal infections since its introduction in the market back in 1958, mainly due to its broad spectrum of activity and low frequency of resistance development [22][23][24][25]. AmB is effective in the treatment of aspergillosis [26], candidiasis [27], blastomycosis [28], paracoccidioidomycosis [29], coccidioidomycosis [28], cryptococcosis [30], histoplasmosis [28], mucormycosis [31], some hyalohyphomycosis [32] and phaeohyphomycosis [33], dermatophytosis [34] and other dermatomycosis [35], sporotrichosis [36], talaromycosis (formerly penicilliosis) [37], and trichosporonosis [38].…”

“…AmB is a macrocyclic lactone with amphiphatic and amphoteric properties due to the presence of hydrophobic polyene and hydrophilic polyol regions, attached to both a carboxylic acid group (pK a 5.7), and a basic mycosamine (pK a 10) sugar (Figure 1). AmB can be either fungistatic or fungicidal depending on fungal susceptibility, drug concentration, and pH, achieving maximum antifungal activity at pH 6.0-7.5 [25,41,42]. However, the high molecular weight of the drug (M r 924.08) and its reduced solubility and permeability contribute to its poor pharmacokinetic profile [25,41,42].…”

“…AmB can be either fungistatic or fungicidal depending on fungal susceptibility, drug concentration, and pH, achieving maximum antifungal activity at pH 6.0-7.5 [25,41,42]. However, the high molecular weight of the drug (M r 924.08) and its reduced solubility and permeability contribute to its poor pharmacokinetic profile [25,41,42]. AmB is also unstable in acid media, sensitive to light and temperature [25,42], requiring storage between 2-8 • C. some parasitic diseases, namely leishmaniasis (cutaneous, mucocutaneous, and visceral) [22,39] and primary amebic meningoencephalitis [22,40].…”

“…However, the high molecular weight of the drug (Mr 924.08) and its reduced solubility and permeability contribute to its poor pharmacokinetic profile [25,41,42]. AmB is also unstable in acid media, sensitive to light and temperature [25,42], requiring storage between 2-8 °C. Due to its amphipathic nature, AmB is able to self-associate in aqueous solution forming water soluble dimers and oligomers that can further associate to form insoluble polyaggregates, which act as a monomer reservoir [25,[43][44][45][46].…”

“…AmB oligomers are particularly toxic to eukaryotic cells leading to high antifungal activity but also severe toxic side effects [43][44][45][46]48,49,51,55] while polyaggregated and monomeric forms of the drug retain antifungal activity and show reduced toxicity towards host cells [43,49,51]. This suggests that better selectivity for fungal cells leading to improved therapeutic index may be achieved by carefully controlling the aggregation state of the drug [25,43,45,46], which can be easily determined from AmB ultraviolet (UV) absorption or fluorescence spectra that are sensitive to different aggregation states [46,56]. Self-association of the drug is related to sequestration of the polyene chromophore within a more hydrophobic environment and the polyene vibronic structure of monomeric AmB collapses to a blue-shifted band typical of aggregated structures [25,57].…”