Studies on freeze-dried drug-milk formulations. II: Effect of regenerated fluid volume on nitrofurantoin bioavailability.

The effect of different milk volumes on the extent and consistency of nitrofurantoin (1-[(5-nitrofurfurylidene)amino]hydantoin) absorption from freeze-dried nitrofurantoin-milk formulations was studied in four male volunteers in three separate crossover designs. Each volunteer received six single-dose treatments (one 100-mg nitrofurantoin capsule with 100, 200, and 400 mL of milk and 100 mg of nitrofurantoin as a freeze-dried nitrofurantoin milk formulation regenerated with 100, 200, and 400 mL of water). Analysis of the urine data revealed superiority of the nitrofurantoin-milk formulations regenerated with 200 and 400 mL of milk over the corresponding capsule formulations in the rates and extents of nitrofurantoin excretion. The binding of nitrofurantoin to casein and bovine serum albumin and its solubility in the presence of the proteins were measured in vitro. The presence of both proteins caused increases in the solubility of nitrofurantoin. Normal protein binding is responsible for the increase of nitrofurantoin solubility in the presence of bovine serum albumin, whereas the increase of nitrofurantoin solubility in the presence of casein is attributed to the formation of aggregates in casein solution at 37 degrees C. The in vivo data were discussed in light of the in vitro data. The freeze-dried nitrofurantoin-milk formulation regenerated with 200 mL of water has a potential for use as a nitrofurantoin delivery system.