Cochleates: New lipid-based drug delivery system

Cochleates are a lipid-based tailored drug delivery system formed by the pr ecipitation of a negatively charged lipid and a cation, for example phospha tidylserine and calcium. Hydrophobic, amphiphilic, negatively or positively charged moieties are suitable candidates to be delivered via cochleates. V arious procedures have been developed allowing the control of cochleate par ticle size, including the trapping and hydrogel methods, which use either a direct addition or a dow diffusion of calcium into the negatively charged liposome/drug suspension. The efficacy of cochleates to encapsulate and del iver drugs was evaluated using amphotericin B as a model. Amphotericin B co chleates (CAMB) were compared to Fungizone(R) and AmBisome(R), two commerci ally available AmB products. Parenterally, CAMB was given IP to ICR mice in fected with Candida albicans. 100% survival was observed with low doses of CAMB (0.5 mg/kg/day, 10 days) compared to 60% for Fungizone, at the same do se. Tissue burden studies were conducted in parallel. Mice were treated dai ly from day 1 to day 7 post challenge and tissue burden assessed at day 8. In the kidneys, all three formulations were comparable in reducing colony c ounts. In the spleen, CAMB at 10 mg/kg/day was comparable to AmBisome given IV at the same dose. At 1 mg/kg/day, CAMB was more potent than Fungizone a nd AmBisome. Oral administration of CAMB in C57BL/6 mice, at 10 mg/kg resul ts in high levels of AmB in target tissues. Multiple daily doses (10) showe d accumulation of AmB in key tissues (liver, lungs, spleen, and kidneys) an d AmB tissue concentrations are raised to therapeutic levels. Orally admini stered CAMB are highly effective against fungal infections in mice at very low doses. Balb/C mice were infected with Candida albicans and were given o ral CAMB as a daily dose for 15 days. Comparison was done to AmBisome given orally at 10 mg/kg and Fungizone IP. 100% survival was obtained with CAMB at doses as low as 0.5 mg/kg/day (15 days). CAMB eradicate Candida from lun gs when given at 2.5 mg/kg/day and was comparable to Fungizone given IP at almost the same dose (2 mg/ kg/day). The comparison between CAMB and AmBiso me shows that oral CAMB is 10 times more effective than oral AmBisome in re ducing colony counts in both kidneys and lungs. Orally administered CAMB we re non-toxic even at the highest dose of 50 mg/kg/day (14 days). This was d emontrated by 100% survival of the animals and normal histopathology analys is. No lesions in the kidneys, GI tract, lungs, liver and spleen was observ ed despite the substantial amount of AmB in these organs. AmB cochleate pro mise to be a safe, broad spectrum, effective and orally available, antifung al formulation.