College of Science, Beijing University of Chemical Technology, Beijing, 100029, China.
Shimadzu (China) Co., LTD., Beijing Branch, Beijing, 100027, China.
AAPS PharmSciTech. 2021 Jan 17;22(1):50. doi: 10.1208/s12249-020-01907-6.
Biological activity and pharmacological efficacy of protein drugs may be affected by the compatibility between drug and packaging materials. The compatibility of rubber closures seal cap has become the focus of many studies due to its complicated formulation. Despite of the significance of the issue, currently, there is little available data about organic leachables in drugs which is also not comprehensive. Since the concentration of migrants in drug is usually low and the matrix is complicated, the establishment of overall profile of extractables is crucial for the characterization of leachables. Herein, the supercritical fluid extraction (SFE) method was used because of its great extraction capacity and efficiency for low to medium polar extractables in rubber stoppers. The SFE conditions were optimized by response surface methodology (RSM). Experimental results of the extract yield were close to the predicted values (R = 0.95). Then the extractables were qualitatively and quantitatively analyzed with ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Finally, risk assessment was made by comparing predicted exposure with injection permitted daily exposure (pPDE) limit or threshold recommended by threshold of toxicological concern (TTC). The results showed that there are many extractables such as glyceride, fatty acids and derivatives, antioxidants, and degradation products. Among them degradation products were in the majority and content of 17 substances exceeded corresponding limits. Considering their unknown toxicology, more experiments are therefore needed to provide information on their toxicology and risk assessment. The study provides a reference for the compatibility of drugs, and quality supervision of pharmaceuticals packaging.
蛋白质类药物的生物学活性和药效学可能会受到药物与包装材料之间相容性的影响。由于橡胶密封盖的配方复杂，其与药物的相容性已成为许多研究的焦点。尽管这个问题意义重大，但目前关于药物中有机浸出物的数据很少，而且也不全面。由于药物中迁移物的浓度通常较低，且基质较为复杂，因此建立浸出物的整体概况对于浸出物的表征至关重要。本文采用超临界流体萃取（SFE）法，因其对低至中等极性的橡胶密封盖提取物具有较强的萃取能力和效率。采用响应面法（RSM）对 SFE 条件进行了优化。萃取产率的实验结果与预测值（R=0.95）非常接近。然后采用超高效液相色谱四极杆飞行时间质谱（UHPLC-QTOF MS）对提取物进行定性和定量分析。最后，通过比较预测暴露量与注射允许日暴露量（pPDE）限值或毒理学关注阈值（TTC）推荐的阈值进行风险评估。结果表明，存在许多浸出物，如甘油酯、脂肪酸及其衍生物、抗氧化剂和降解产物。其中降解产物居多，有 17 种物质的含量超过了相应的限度。考虑到它们未知的毒理学性质，因此需要进行更多的实验，以提供关于它们的毒理学和风险评估的信息。本研究为药物的相容性和药品包装的质量监督提供了参考。
