硅是药包材和含硅生产组件常监控的浸提沥滤物元素之一。在药包材相容性研究中,药物尤其是药液与含硅包装系统(如玻璃、硅胶)之间存在相互作用,近年来国家药监局药品审评中心也要求研究药液中硅元素的含量以预测玻璃内表面脱片趋势,因此硅在药品包装中的安全使用亟待评估,相关毒性阈值也受到关注。口服途径方面,无机硅例如二氧化硅、有机硅例如硅胶管/硅油的主要成分聚二甲基硅氧烷(PDMS)的毒性均较低;吸入途径方面,二氧化硅可能会引起硅肺病甚至肺癌;注射给药途径下,二氧化硅或玻璃、硅油/硅胶管聚合物寡聚体的毒性与它们的形态或聚合度有关。总的来说,有机硅的分子量决定了其毒性特征与强度:比如大分子聚合物PDMS的腹腔或皮下注射未发现明显毒性,但PDMS无法降解和排泄;然而,PDMS静脉注射途径下可致死,小分子二甲基硅氧烷也会有高毒及致死剂量。基于多个毒理学数据,推导获得无机硅和有机硅最保守情况下的毒理学阈值(允许日暴露量,PDE)分别为93和100 μg·d-1。根据文献,推算不同形式的硅元素不同给药途径下的PDE值供药企和监管机构参考。
Silicon is one of the most monitored inorganic elements in extractables and leachables (E&L) studies of pharmaceutical packaging systems and related components. There is an urgency to evaluate toxicological threshold of silicondueto the direct contact of drug products (DP) especially a liquid form of DP with thewidely used pharmaceutical packaging systems made of silicon materials, for instance, glass and silicone. It is also required by the Center for Drug Evaluation (CDE) of National Medical Products Administration in China to test thesilicon content in DP to investigate glass delamination in E&L studies. Specifically, oral toxicity is low for inorganic silicon like silicon dioxide or organic silicon polymers such as silicon tube/silicone oil (polydimethylsiloxane, or namely PDMS as the major ingredient).In comparison, inhalational toxicity of silicon dioxide leads to pulmonary silicosis or even lung cancer. In the case of the parenteral route of administration, the toxicity of silicon dioxide, glass, polymers or PDMS oligomers varies depending on their morphology or degrees of polymerization. Overall, the toxicities of organic silicon compounds vary due to their different molecular weight (MW). PDMS with high MW has minimal toxicsymptoms by both intra-peritoneal and subcutaneous administration routes, yet it is worth noting the difficulty of degradation and elimination of PDMS. For intravenous administration route, exposure to either PDMS or small molecule dimethyl silicone compoundsmay lead to death. Finally, our work determines permitted daily exposure (PDE) of 93 μg·d-1 for inorganic silicon and 100 μg·d-1 for organic silicon by reviewing toxicological data of both forms of silicon. This work aims to provide evidences and references for pharmaceutical companies and regulatory agencies on the PDEs of silicone elements through a variety ofadministration routes.
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