Studies on drug-milk freeze-dried formulations. I: Bioavailability of sulfamethizole and dicumarol formulations.
In this study, solid dispersion formulations of dicumarol (3,3'-methylenebis[4-hydroxycoumarin]) and sulfamethizole (N'-(5-methyl-1,3, 4-thiadiazol-2-yl)sulfanilamide) in defatted milk were prepared by freeze-drying. X-ray crystallographic data showed that both drugs were dispersed in the formulations in an amorphous state. Bioequivalency comparisons between freeze-dried formulations, after regeneration with water, and control capsules containing the pure drug substances were studied in four male volunteers. Determination of the plasma dicumarol levels indicated superiority of the dicumarol-milk formulation. Statistically significant differences were found between area under the curve, maximum plasma concentration, and apparent elimination rates. Analysis of the urine sulfamethizole data revealed that the two formulations exhibit statistically equivalent rates and extents of excretion of unchanged sulfamethizole. The binding of both drugs to casein and their solubility in the presence of casein were measured in vitro. The presence of casein caused an increase in the solubility of dicumarol, while it had no effect on the solubility of sulfamethizole. Normal protein binding cannot be responsible for the effects noted. Extrapolation of the in vitro data to the in vivo situation was attempted. Drug-milk freeze-dried formulations are promising for the enhancement of the bioavailability of sparingly water soluble drugs.
D000328:Adult; D000818:Animals; D001682:Biological Availability; D001728:Dicumarol / Q000008:administration & dosage / Q000378:metabolism*; D005612:Freeze Drying; D006801:Humans; D008297:Male; D008892:Milk; D010316:Particle Size; D014677:Pharmaceutical Vehicles; D011485:Protein Binding; D012995:Solubility; D013419:Sulfamethizole / Q000008:administration & dosage / Q000378:metabolism*; D013432:Sulfathiazoles / Q000378:metabolism*; D014961:X-Ray Diffraction
D014677:Pharmaceutical Vehicles; D013432:Sulfathiazoles; D013419:Sulfamethizole; D001728:Dicumarol