Efficacy evaluation of a novel submicron miconazole emulsion in a murine cryptococcosis model.
Submicron emulsions of miconazole were stabilized by using a combination of three emulsifiers comprising phospholipids, poloxamer, and deoxycholic acid (DCA). The presence of DCA was vital for prolonged emulsion stability owing to its contribution to the elevated zeta potential of the emulsion. Further, the results by the phospholipid surface labelling colorimetric technique clearly suggested that poloxamer molecules interacted with phospholipid polar-head groups of the mixed DCA-phospholipid interfacial film, resulting in the stabilization of the emulsion by a steric enthalpic entropic mechanism. The plain emulsion vehicle was well tolerated up to a dose of 0.6 ml injected i.v. to BALB/c mice. The maximum tolerated dose of miconazole was 80 and 250 mg/kg in Daktarin i.v. (a marketed product) and emulsion, respectively, showing an improved safety ratio of 1 to 3 in favor of the emulsion. These results tended to confirm that the adverse effects associated with Daktarin i.v. injection should be associated with the vehicle rather than with the miconazole itself. In a murine cryptococcosis model, only one mouse out of ten remained alive by day 15 in the infected group treated with Daktarin i.v., while in the miconazole emulsion treated group, mice began to die from day 16 up to day 25 post inoculation. Thus, the multiple-dose treatment with the miconazole emulsions improved the protection offered to the infected mice. However, the therapeutic levels of miconazole that were reached in the target organ (brain) were lower than those required for complete eradication of Cryptococcus neoformans, which is known to multiply preferentially in the brain.
Levy
M Y
MY
Department of Pharmacy, School of Pharmacy, Hebrew University of Jerusalem, Israel.
Polacheck
I
I
Barenholz
Y
Y
Benita
S
S
D000818:Animals; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D003840:Deoxycholic Acid / Q000737:chemistry; D004355:Drug Stability; D004655:Emulsions; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008825:Miconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D011060:Poloxalene / Q000737:chemistry; D014302:Trinitrobenzenesulfonic Acid
D004655:Emulsions; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D003840:Deoxycholic Acid; D008825:Miconazole; D014302:Trinitrobenzenesulfonic Acid; D011060:Poloxalene