Muriel Eaton1,2, Zhefu Que1,2, Jingliang Zhang1,2, Kaethe Beck3, Riyi Shi2,4, Jeff McDermott5, Michael Ladisch6, Yang Yang7,8. 1. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, Hall for Discovery and Learning Research (DLR), 207 S Martin Jischke Dr., West Lafayette, Indiana, USA. 2. Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana, USA. 3. Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana, USA. 4. Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA. 5. Eli Lilly and Company, Delivery Devices and Connected Solutions, Indianapolis, Indiana, USA. 6. Department of Agricultural and Biological Engineering, College of Engineering; Weldon School of Biomedical Engineering; and Laboratory of Renewable Resources Engineering (LORRE), Purdue University, 225 S. University Street, West Lafayette, Indiana, USA. ladisch@purdue.edu. 7. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, Hall for Discovery and Learning Research (DLR), 207 S Martin Jischke Dr., West Lafayette, Indiana, USA. yangyang@purdue.edu. 8. Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana, USA. yangyang@purdue.edu.
Abstract
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.
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.
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