A novel heparin-coated hydrophilic preparation of amphotericin B hydrosomes.

Amphotericin B Hydrosomes (AH; Access Pharmaceuticals Inc) are a novel formulation of hydrophilic, heparin-surfaced nanoparticles (mean diameter 105 nm) containing amphotericin B (AmB) designed to target infected sites by local adhesion. AH are cleared in part by a hepatobiliary mechanism, which results in a reduction of AmB concentration in major organs by about 50% in 24 h. In mice with pulmonary blastomycosis, unlike Fungizone (Bristol-Myers Squibb Inc), a deoxycholate micellar formulation of AmB, AH accumulates 3-fold more in infected lungs than normal lungs, between 3 and 24 h post-injection. Histologically, AH accumulates at the sites of lesions. AH is approximately 7-fold less toxic than Fungizone based on acute lethality and histopathological assessment of renal damage. In vitro, AH and Fungizone were equally active against Blastomyces dermatitidis and in vivo they were equivalent in prolonging mouse survival, when compared with equal dosing of AmB. In reducing infectious burdens in vivo, Fungizone was 3-fold more effective than AH on a mg/kg basis of administered AmB. However, AH at 4.8 mg/kg cured 50 to 60% of mice, whereas Fungizone at a near lethal dose of 1.2 mg/kg cured none. The AH formulation of AmB has an improved therapeutic index, relative renal-site avoidance and selective accumulation in infected tissues, which combine to merit additional studies in appropriate fungal models.