Cyclodextrin inclusion complexes of miconazole and econazole - isolation, toxicity on human cells, and confirmation of a new interpretation of the drug supersaturation phenomenon

Parameters that influence the precipitation of the beta-cyclodextrin (beta- CD) inclusion complexes of the antimycotics miconazole and econazole were i nvestigated. The mechanistic reason for the superior antimycotic activity o f the miconazole inclusion complex was studied The toxicity of the complex was estimated. The temperature, the buffer strength, and the effect of the addition of hydrotropic agents on the CD solubility diagrams far the antimy cotics were estimated The miconazole and the CD dissolution rate for the co mplex was measured. The hemolytic activity of the miconazole inclusion comp lex, the physical mixture, miconazole, and the nitrate salt were compared. The toxicity on TR146 oral cell layers was measured. Lowering the temperatu re meant that both complexes precipitated at lower CD concentrations. Addit ion of hydrotropic agents and variation of the buffer strength affected the solubility diagrams. The dissolution medium was supersaturated with micona zole. The supersaturation was not disclosed by the traditional method to an alyze for drug supersaturation. The miconazole complex was more toxic to er ythrocytes than the physical mixture. On the other hand, the toxic effects of the two products on the TR146 cell layers were similar. Lowering the tem perature eased the isolation of genuine CD inclusion complexes of miconazol e and econazole. The miconazole supersaturation is likely to be the reason for the superior antimycotic activity of the complex. The complex and the p hysical mixture had about the same toxicity on TR146 cell layers.