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 investigated. The mechanistic reason for the superior antimycotic activity of 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 for the antimycotics were estimated. The miconazole and the CD dissolution rate for the complex was measured. The hemolytic activity of the miconazole inclusion complex, the physical mixture, miconazole, and the nitrate salt were compared. The toxicity on TR146 oral cell layers was measured. Lowering the temperature meant that both complexes precipitated at lower CD concentrations. Addition of hydrotropic agents and variation of the buffer strength affected the solubility diagrams. The dissolution medium was supersaturated with miconazole. The supersaturation was not disclosed by the traditional method to analyze for drug supersaturation. The miconazole complex was more toxic to erythrocytes than the physical mixture. On the other hand, the toxic effects of the two products on the TR146 cell layers were similar. Lowering the temperature eased the isolation of genuine CD inclusion complexes of miconazole and econazole. The miconazole supersaturation is likely to be the reason for the superior antimycotic activity of the complex. The complex and the physical mixture had about the same toxicity on TR146 cell layers.
Pedersen
M
M
PEDCY, Lemvig, Denmark.
Jacobsen
J
J
Sørensen
A M
AM
D000935:Antifungal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival; D003505:Cyclodextrins / Q000737:chemistry*; D004347:Drug Interactions; D004464:Econazole / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008825:Miconazole / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D009055:Mouth / Q000166:cytology; D009566:Nitrates / Q000633:toxicity; D012995:Solubility; D013696:Temperature; D014867:Water / Q000032:analysis; D047392:beta-Cyclodextrins
D000935:Antifungal Agents; D003505:Cyclodextrins; D009566:Nitrates; D047392:beta-Cyclodextrins; D014867:Water; D004464:Econazole; D008825:Miconazole; C031215:betadex