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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 the capsule of cabazitaxel lipid microsphere (CTX-LM) injection on the stability of the preparation and to discuss the mechanism of drug degradation in the preparation. Methods Under accelerated conditions, the drug content, particle size, p H value, residual oxygen and total oxidation were measured. Results Residual oxygen had no effect on the solid raw material of cabazitaxel. The content of residual oxygen was 99.8%, 99.8% and 99.9% at 40, 60 and 80 ℃, respectively. There was no obvious change in residual oxygen. Under high temperature, Aqueous solution of drug content mass fraction decreased to 40.4%, but has nothing to do with residual oxygen. For the injection of cabazitaxel lipid microsphere, the hypoxia group was less oxidized than the hyperoxia group at high temperature, and its chemical stability was better. The degradation activation energies were 62.6 kJ · mol-1 and 56.1 kJ · mol- 1. The mechanism is that the unsaturated fatty acid side chain of the phospholipid is oxidized and broken by the residual oxygen to generate acidic oxidation products to decrease the p H value of the system, which aggravates the hydrolysis of the cabazitaxel in the weak acid condition, and the more the residual oxygen is, the higher the temperature is, Degradation is more significant. Conclusion Control of residual oxygen in the container helps to improve the stability of the injection of captopril lipid microsphere.