Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, United States of America.
Departments of Medicine and Pharmacy, University of California, San Francisco, California, United States of America.
PLoS One. 2020 Jun 25;15(6):e0235076. doi: 10.1371/journal.pone.0235076. eCollection 2020.
Due to the complexity and fragility of biological drug products, several challenges exist in their formulation development. Excipients are added to increase product stability, maintain tonicity, and facilitate drug delivery. The potential implications of these additive substances merit clinical consideration. We assessed the safety risk of excipients on the basis of their type and variability through an assessment framework, which quantifies excipient complexity in 230 biological formulations, and identifies excipient-related adverse events through published case reports. A biologic on average contained 4.45 excipients, half of that found in oral medications. The frequency distribution was heavily skewed towards the most commonly occurring excipients: water (40.4%), sodium chloride (38.3%), polysorbate 80 (28.7%), sucrose (24.4%), and mannitol (20.9%), with 44.4% of formulations not listing the concentration of the most commonly occurring inactive ingredients. A literature search revealed only 17 case reports of excipient-related adverse events, suggesting the need for more clarity for clinicians on the safety of chemical additives. These cases included injection site reactions, anaphylaxis, hyperglycemia, and acute renal failure. With the expansion of the biopharmaceutical market, it is important to consider the safety data of biologic excipients, so that therapy can be tailored appropriately for a specific patient.
由于生物药物产品的复杂性和脆弱性，其制剂开发存在若干挑战。赋形剂的添加可以提高产品稳定性、维持等渗性并促进药物传递。这些添加剂物质的潜在影响值得临床关注。我们根据赋形剂的类型和变异性，通过评估框架评估赋形剂的安全性风险，该框架对 230 种生物制剂中的赋形剂复杂性进行量化，并通过已发表的病例报告识别与赋形剂相关的不良事件。一种生物制剂平均含有 4.45 种赋形剂，是口服药物的一半。频率分布严重偏向于最常见的赋形剂：水（40.4%）、氯化钠（38.3%）、聚山梨酯 80（28.7%）、蔗糖（24.4%）和甘露醇（20.9%），44.4%的制剂未列出最常见的非活性成分的浓度。文献检索仅发现 17 例与赋形剂相关的不良事件报告，这表明临床医生需要更清楚地了解化学添加剂的安全性。这些病例包括注射部位反应、过敏反应、高血糖和急性肾衰竭。随着生物制药市场的扩张，考虑生物制剂赋形剂的安全性数据非常重要，以便为特定患者量身定制治疗方案。
