在雾化抗体织物碎片时最小化聚合物:高热稳定性和高度是关键因素
Josi Ann Steinke1, Pierre-Louis Destruel2, Benjamin Weiche3
1Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM, Nikolai-Fuchs-Str. 1, Hannover, 30625, Germany.
概括
高蛋白质稳定性和度是防止在雾化期间在吸入的抗体碎片中聚合的关键. 使用高化温度 (>80°C) 和高度 (≥40 mg/mL) 的抗体片段来配制,可确保稳定性并降低免疫性风险.
科学领域:
- 生物制药配方 生物制药配方
- 蛋白质聚合蛋白质的聚合.
- 吸入药物输送是吸入药物输送.
背景情况:
- 吸入生物制剂的治疗潜力受到空气化过程中蛋白质不稳定的阻碍.
- 在雾化过程中蛋白质聚合可以增加免疫性和安全风险.
- 抗体碎片 (Fabs) 是有希望的吸入疗法,但需要稳定的配方.
研究的目的:
- 确定关键的分子和配方参数,以尽量减少在振动网雾化过程中抗体Fab片段聚合.
- 评估Fab热稳定性,蛋白质度,辅料和雾化器装置对聚合的影响.
主要方法:
- 通过使用两台商用振动网状雾化器,评估了14个具有不同化温度 (Tm60-90°C) 的工程Fab.
- 评估了高分子量物种 (HMWS) 和低可见粒子 (SVP) 的形成.
- 分析了气溶的特性,包括微粒分数 (FPF) 和输出速度.
主要成果:
- 高固有的热稳定性 (Tm > 80°C) 和高蛋白质度 (10-80 mg/mL) 显著降低了聚合.
- 增加的蛋白质度通过和空气/液体界面来抑制聚合,特别是对于不太稳定的Fabs来说.
- 较高度增加了可吸入蛋白质的输出,尽管雾化器输出率略有降低.
结论:
- 选择具有高热稳定性 (Tm>80°C) 的Fabs,并以高度 (≥40 mg/mL) 配制,对于稳定的吸入式Fab疗法至关重要.
- 这些策略减轻了聚合诱导的免疫性和安全问题.
- 促进下一代吸入式蛋白质药物的开发.
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