非PVC聚烯烃药品包装材料安全性全息鉴别技术研究

Small molecules in pharmaceutical packaging materials can migrate into medicine while in contact with them during storage and shelf life, which may react with medicine, affect its efficacy and even generate adverse drug reaction (ADR). Therefore, safety study on pharmaceutical packaging materials has been attracting increasing attention. However, the diversity of matrices of packaging material and the complexities of formulations pose great challenges to safety study. This project will focus on the safety of non-PVC polyolefin pharmaceutical packaging materials. Fabric phase sorptive extraction, an innovative sample preparation will be used to enrich all different polar extractables at the same time. The sample will be analyzed by multi-dimensional and multi-mode of hyphenated techniques to build the database of the extractables including chromatographic retention time, accurate mass and mass spectral cleavage laws; The toxicological data of extractables are predicted by toxicology software and toxicological evaluation database will be established; The mixed toxicity of extractables to cells will be studied with toxicated biological cells and the toxicity mechanism will be elaborated by utilizing metabolomics; The migration kinetic model of extractables will be built using molecular dynamics（MD） simulation method. This project will realize high throughput accurate detection for extractables in pharmaceutical packaging materials, and provide a database of toxicological evaluations and migration prediction model of extractables, which will eventually contribute supports to quality control and risk control of pharmaceutical packaging materials.

药品包装材料中的小分子物质在与药品接触过程中可能迁移进入药品，与药物发生反应，影响药物效果，甚至产生毒副作用，因此药包材的安全性研究得到广泛关注。但是，药包材基质的多样性和配方的复杂性，为其安全性研究带来极大挑战。本项目拟以非PVC聚烯烃药品包材为研究对象，建立包含添加剂等迁移物的色谱保留时间、质谱精确质量数和质谱裂解规律的高分辨质谱筛查数据库；开发多重机制的膜固相微萃取样品同步提取净化技术；利用多维多模式全息识别方法筛选各种包装材料迁移物的高特征组分；结合毒理学软件预测迁移物各成分的毒理学数据，建立毒理评价数据库；通过染毒生物细胞，研究迁移物的细胞混合毒性，利用代谢组学方法阐述毒性作用机制；采用分子动力学模拟迁移行为，探究迁移物的迁移动力学模型。本研究能实现药包材中迁移物的高通量的精准检测，提供迁移物的毒理评价数据库和预测模型，为药包材质量控制和风险评估提供支撑。

收集了国内外各种非PVC聚烯烃多层共挤输液袋和弹性体密封件材料并开展了系统的E&L研究，得到了较详细的可提取物清单，结合其理化信息、检测信息建立了E&L筛查数据库，由此可实现药包材中可提取物的高通量精准检测；研究了密封件材料在γ-射线辐照过程中产生的降解产物，并采用DFT密度泛函理论计算进行了结构验证。针对包括添加剂和降解产物在内的E&L，利用Python爬虫技术从毒性数据库和文献中搜索其毒性数据，结合毒理学软件预测结果建立了毒理评价数据库，并建立了毒性分级评估策略及风险矩阵。进一步开展了细胞毒性试验和迁移动力学的探究；通过溶胶-凝胶法将聚二甲基硅氧烷（PDMS）涂覆在纯棉纤维布上制备织物萃取，优化了影响萃取效率的关键因素，结合超高效液相色谱-四极杆飞行时间质谱法（UHPLC-QTOF-MS）测定藿香正气水口服液瓶（高密度聚乙烯材质）在与不同pH溶液接触中的可提取物，实际药液的分析中实现了霍香正气水中浸出物的靶向检测，检出了４种浸出物并开展了定量分析。进一步基于Toxtree 软件和T.E.S.T 软件进行了浸出物的风险评估，4种浸出物的每日摄入量均未超过成人每日允许暴露量，说明藿香正气水中的浸出物含量处于相对安全的水平。开展了预灌封注射器和预灌封注射笔的相容性研究。

内容获取失败，请点击重试