组氨酸缓冲液中英夫利西单抗的稳定性评价

Evaluation of Effects of Histidine Buffer on the Stability of Infliximab Formulation

关键词:  英夫利西单抗，缓冲剂，物理稳定性，冷冻稳定性，组氨酸

Key words:  infliximab, buffering agent, physical stability, diffusion interaction parameter, freeze-thaw, stability

摘要:

摘要：目的 本研究旨在筛选出适用于英夫利西单抗(Infliximab)制剂的更优缓冲剂，并进一步评估其物理稳定性和冷冻稳定性。方法 本研究涉及两种主要缓冲剂—组氨酸和磷酸盐，同时评估了不同pH值、稳定剂和表面活性剂对英夫利西单抗聚体含量的影响。进一步对组氨酸和磷酸盐缓冲剂中英夫利西单抗在物理稳定性及冷冻过程中的变化进行了详细分析。结果 实验数据显示，在液体制剂中，以组氨酸为缓冲剂的英夫利西单抗聚体含量更低，展示出更高的稳定性。其物理稳定性指标，包括熔融温度(melting temperature, Tm)、聚集温度(aggregation onset temperature, Tagg)和扩散相互作用系数(diffusion interaction coefficient, kD）均优于磷酸盐体系；冻干稳定性指标，冻干制剂的玻璃态转化温度(glass transition temperature, Tg)和液体状态最大冷冻浓缩溶质的玻璃态转化温度(glass transition temperature of maximally freeze concentrated solution, Tg′)在两种缓冲体系中均未表现统计学差异。在冻干制剂中，磷酸盐体系在冷冻过程中的pH值发生显著波动，而组氨酸则保持稳定。结论 综合以上实验结果，组氨酸被选为英夫利西单抗制剂的更优缓冲剂，并有较好的物理稳定性。

Abstract:

ABSTRACT: OBJECTIVE The study aims to identify the optimal buffering agent suitable for Infliximab formulations and to further evaluate its physical and freeze-thaw stability. METHODS The study involves two primary buffering agents—histidine and phosphate, and assesses the impact of varying pH levels, stabilizers, and surfactants on the aggregation content of Infliximab. A detailed analysis was performed to evaluate the physical and freeze-thaw stability of Infliximab in formulations containing histidine and phosphate buffers. RESULTS Experimental data indicate that in liquid formulations, Infliximab with histidine as the buffering agent exhibited lower aggregation content and higher stability. Its physical stability parameters, including melting temperature (Tm), aggregation onset temperature (Tagg), and diffusion interaction coefficient (kD) were superior to those in the phosphate system; the freeze-drying stability parameter (glass transition temperature of maximally freeze concentrated solution, Tg’) and the glass transition temperature (Tg) were not expressed statistically significant difference between the two buffer systems. In lyophilized formulations, the phosphate buffer system exhibited significant pH fluctuations during the freeze-thaw process, whereas the histidine buffer remained stable. CONCLUSION Based on the comprehensive experimental results, histidine was selected as the optimal buffering agent for Infliximab formulations and demonstrating superior physical stability.