摘要
目的考察卡巴他赛脂质微球(cabazitaxel lipid microsphere,CTX-LM)注射液容器内残氧量对制剂稳定性的影响,并讨论制剂中药物的降解机制。方法在加速条件下,测定药物含量,制剂粒径、p H值、残氧量、全氧化值等指标。结果残存氧对卡巴他赛固体原料药无降解作用,40、60和80℃加速10 d的含量质量分数分别为99.8%、99.8%和99.9%,残氧量无明显变化;高温条件下卡巴他赛水溶液药物含量质量分数降低至40.4%,但与残存氧无关。对于卡巴他赛脂质微球注射液,高温下低氧组制剂氧化程度小于高氧组,且化学稳定性更好,降解活化能分别为62.6 k J·mol-1和56.1 k J·mol-1。其机制为磷脂的不饱和脂肪酸侧链经残存氧氧化断裂,产生酸性氧化产物使体系p H值下降,加剧了卡巴他赛在弱酸条件的水解,且残存氧越多、温度越高时,药物降解越显著。结论控制容器内残氧量有助于提高卡巴他赛脂质微球注射液的稳定性。
Objective To investigate the effect of residual oxygen in vials on the stability of cabazitaxel lipid microsphere( CTX-LM) and the degradation mechanism of cabazitaxel in lipid microsphere. Methods In acceleration test,drug content,particle size,p H,residual oxygen and the full oxidation value were measured.Results After acceleration test of 10 days,residual oxygen was constant and the content of CTX stored at 40,60 and 80 ℃ was 99. 8%,99. 8% and 99. 9%,respectively. The content of cabazitaxel in aqueous solution reduced to 40. 4%,which was independent of residual oxygen. CTX-LMwith lowresidual oxygen demonstrated more stable and more hardly to be oxidated than that with high residual oxygen,the Ea of degradation was 62. 6 kJ·mol^-1 and 56. 1 kJ·mol^-1,separately. In the presence of residual oxygen,the unsaturated fatty acid side chains of lecithin were prone to break,then its acid oxidation products would decrease the pH of CTX-LM,which could promote hydrolysis of cabazitaxel. The higher residual oxygen and temperature,the more cabazitaxel was degraded. Conclusions To limit the residual oxygen in vials could improve the stability of CTX-LM.
出处
《沈阳药科大学学报》
CAS
CSCD
北大核心
2016年第12期932-937,944,共7页
Journal of Shenyang Pharmaceutical University
关键词
卡巴他赛
脂质微球
残氧量
氧化
稳定性
cabazitaxel
lipid microsphere
residual oxygen
oxidation
stability