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

被引:70
作者
Bhagwatwar, HP
Phadungpojna, S
Chow, DSL
Andersson, BS
机构
[1] UNIV TEXAS,MD ANDERSON CANC CTR,DEPT HEMATOL,HOUSTON,TX 77030
[2] UNIV HOUSTON,COLL PHARM,BS ANDERSSON DEPT PHARMACOL & PHARMACEUT SCI,HOUSTON,TX
关键词
busulfan; intravenous formulation; parenteral formulation; high-dose chemotherapy; malignant disease;
D O I
10.1007/s002800050404
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The bifunctional alkylating a ent 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.
引用
收藏
页码:401 / 408
页数:8
相关论文
共 45 条
[1]  
[Anonymous], 1968, Br Med J, V1, P201
[2]  
ARLIN ZA, 1980, CANCER RES, V40, P3304
[3]  
BERAN M, 1987, CANCER RES, V47, P1897
[4]  
BESCHORNER WE, 1980, AM J PATHOL, V99, P369
[5]  
Bhagwatwar H. P., 1994, Proceedings of the American Association for Cancer Research Annual Meeting, V35, P298
[6]  
BHAGWATWAR HP, IN PRESS J CHROMATOG
[7]  
CANELLOS GP, 1975, BLOOD, V45, P197
[8]  
CANELLOS GP, 1985, CANCER PRINCIPLES PR, P1739
[9]  
CHAMPLIN RE, 1985, TRANSPLANT P, V17, P496
[10]  
CHAO NJ, 1993, BLOOD, V81, P319