Purpose

Pharmaceutical buffer systems, especially for injectable biologics such as monoclonal antibodies, are an important component of successful FDA-approved medications. Clinical studies indicate that buffer components may be contributing factors for increased injection site pain.

Methods

To determine the potential nociceptive effects of clinically relevant buffer systems, we developed an in vitro multi-electrode array (MEA) based recording system of rodent dorsal root ganglia (DRG) sensory neuron cell culture. This system monitors sensory neuron activity/firing as a surrogate of nociception when challenged with buffer components used in formulating monoclonal antibodies and other injectable biologics.

Results

We show that citrate salt and citrate mannitol buffer systems cause an increase in mean firing rate, burst frequency, and burst duration in DRG sensory neurons, unlike histidine or saline buffer systems at the same pH value. Lowering the concentration of citrate leads to a lower firing intensity of DRG sensory neurons.

Conclusion

Increased activity/firing of DRG sensory neurons has been suggested as a key feature underlying nociception. Our results support the utility of an in vitro MEA assay with cultured DRG sensory neurons to probe the nociceptive potential of clinically relevant buffer components used in injectable biologics.

中文翻译：

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感觉神经元的多电极阵列作为体外平台来识别对注射生物制剂药物缓冲系统的伤害性反应

目的

药物缓冲系统，尤其是单克隆抗体等可注射生物制剂，是获得 FDA 批准的成功药物的重要组成部分。临床研究表明，缓冲液成分可能是导致注射部位疼痛加剧的因素。

方法

为了确定临床相关缓冲系统的潜在伤害性影响，我们开发了一种基于体外多电极阵列 (MEA) 的啮齿动物背根神经节 (DRG) 感觉神经元细胞培养记录系统。当受到用于配制单克隆抗体和其他可注射生物制剂的缓冲液成分的挑战时，该系统监测感觉神经元活动/激发作为伤害感受的替代物。

结果

我们表明柠檬酸盐和柠檬酸甘露醇缓冲系统导致 DRG 感觉神经元的平均放电率、爆发频率和爆发持续时间增加，这与相同 pH 值的组氨酸或盐水缓冲系统不同。降低柠檬酸盐的浓度会导致 DRG 感觉神经元的放电强度降低。

结论

DRG 感觉神经元的活动/放电增加被认为是伤害感受的关键特征。我们的结果支持体外MEA 测定与培养的 DRG 感觉神经元的效用，以探测可注射生物制剂中使用的临床相关缓冲液成分的伤害感受潜力。