缩宫素注射液的有关物质研究

目的: 针对缩宫素注射液现行标准中未对注射液中有关物质进行控制的情况,建立了缩宫素注射液有关物质的HPLC测定法,并对2010年国家评价性抽验中178批缩宫素注射液样品进行了测定。 方法: 采用Agilent ZORBAX SB-C₁₈ 色谱柱(250 mm×4.6 mm,5 μm);以0.1 mol·L^-1 磷酸盐缓冲液作为流动相A,以水-乙腈(1∶ 1)作为流动相B,梯度洗脱,柱温40 ℃,流速为1.0 mL·min^-1,检测波长为220 nm。 结果: 在本文色谱条件下,主峰和杂质峰能得到良好的分离;缩宫素在浓度0.36~23.04 IU·mL^-1 范围内峰面积与浓度呈良好线性关系,r=0.9999;平均回收率99.1%(n=9)。178批缩宫素注射液总杂质为25.9%~36.0%,单个最大杂质为6.1%~13.0%。 结论: 该法专属性强,灵敏、准确,可作为缩宫素注射液的质量控制方法。现行标准不能有效控制药品质量,体现在有关物质偏高。研究表明制剂中的有关物质部分是由原料引入,因此,必须修订并提高原料和制剂的质量标准,增加有关物质检查。建议原料生产企业采用固相合成工艺的缩宫素提高原料质量,加强生产过程中各个环节的质量意识。

Objective: A selective gradient liquid chromatographic method for the determination of oxytocin and its related substances has been developed and applied to analyze 178 batches of commercial oxytocin injection samples. Methods: An Agilent ZORBAX SB-C₁₈ column (250 mm×4.6 mm,5 μm) was used for the gradient elution.The mobile phases consisted of 0.1 mol·L^-1 dihydrogen phosphate solution (adjust to pH 6.0) - acetonitrile (50∶ 50).The flow rate was 1.0 mL·min^-1 .UV detection was performed at 220 nm,and the column temperature was set to 40 ℃. Results: Oxytocin and its related substances were successfully detected by the established method.The method showed good resolution and linearity between peak area and oxytocin concentration at the range of 0.36-23.04 IU·mL^-1 with r=0.9999. The average recoveries(n=9) was 99.1%.In 178 batchs of commercial oxytocin injection samples,the total content of impurity range from 25.9% to 36.0%,the largest content of single impurity range from 6.1% to 13.0%. Conclusion: The method is proved to be specific,sensitive and accurately and could be used to control the quality of oxytocin injection.Furthermore,the method proved to be successful when applied to analyze 178 batches of commercial oxytocin injection samples.The research suggests that the existing standards is in deficiencies,and need to be improved immediately by using more proprietary methods such as HPLC to control and check the quality of drugs.Most of the impurities in the oxytocin injections are related to the raw materials and the raw materials produced by solid-phase peptide synthesis method should be used by guiding the enterprises.