Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy.

The bifunctional alkylating agent busulfan (Bu) was solubilized in a cosolvent mixture of anhydrous dimethylacetamide (DMA), polyethylene glycol 400 (PEG400), and water at a ratio of 1:2:2 (v/v/v), to achieve a Bu concentration of 3 mg/ml, a preparation that would be suitable for parenteral administration in high-dose chemotherapy preceding bone marrow transplantation. The complete formulation was stable for more than 54 h at room temperature (RT, 22 degrees C). An accelerated stability study of Bu in anhydrous DMA or DMA/PEG400 (1:2) as stock solutions indicated shelf-lives of 191 and 180 days respectively, at RT, and 8.2 and 7.5 years, respectively, at 4 degrees C. Although the complete formulation with Bu was very hypertonic, hemolysis studies indicated that the formulation would be safe for intravenous (i.v.) administration, since it would be rapidly diluted to harmless tonicity levels in the blood. Cytotoxicity studies of the complete formulation in vitro proved that Bu retained its activity when dissolved in the complete vehicle. A preliminary pharmacokinetic study in a rodent model after the i.v. administration of Bu at a dose of 1 mg/kg body weight yielded high plasma concentrations of Bu for at least 5 h after injection.