中文摘要：

重组人粒细胞刺激因子是一种非常重要的重组蛋白质药物,它容易发生蛋白质氧化。采用反相色谱法测定37℃加速试验和4℃长期稳定性试验中该产品的纯度变化,研究其保藏过程中的化学稳定性。考察了添加氧化剂和还原剂对产品的短期和长期稳定性作用,结果表明所有氧化剂包括过氧化氢和亚硝酸盐都具有较强的浓度效应而还原剂具有较强的pH依赖性。当亚硝酸盐浓度大于0.1 ppm时,具有明显的氧化作用。进一步考察了不同包装材料和过渡态金属离子对化学稳定性的作用。安瓿瓶火焰融封时会导致过渡态金属离子的溶出,结果表明亚铁离子催化活性最强,在0.05 ppm浓度下就具有明显的氧化作用。加入抗氧化剂L-Met能在一定程度上降低长期保藏过程中化学不稳定性,而添加金属螯合剂EDTA二钠能够明显提高该重组蛋白药物的化学稳定性。

英文摘要：

The recombinant human granulocyte colony stimulating factor（rhG-CSF） is an important recombinant protein drug;however the rhG-CSF is liable to be oxidized.The reversed-phase chromatography was used to measure the purity of rhG-CSF in 37℃ accelerated stability and 4℃ long-term stability assays.The oxidant and reductant with different concentrations were added to the rhG-CSF products to evaluate their short-term and long-term effects on the stability of rhG-CSF.It was found that all oxidants including hydrogen peroxide and nitrite sodium have a strong concentration effect on the oxidation process,and the reducing agents have strong pH dependence.The protein oxidation is obvious when the concentration of nitrite is higher than 0.1 ppm.The effects of different types of package material and transition metal ions on protein stability were evaluated.The results show that trace amounts of transition metal ions would be released during the sealing of ampoule with flame fusion,and the ferrous ions（Fe2＋） released have the strongest catalytic activity,and even if the released Fe2＋ concentration is 0.05 ppm,the rhG-CSF oxidation is obvious.It was also found that the addition of EDTA（Edetate disodium） and L-Met can inhibit rhG-CSF oxidation to a certain degree during its long-term preservation.The experiments show that adding EDTA would improve the stability of rhG-CSF more significantly.