Dynamic Properties of Novel Excipient Suggest Mechanism for Improved Performance in Liquid Stabilization of Protein Biologics

Abstract

To improve liquid formulation stability, formulators employ various excipients designed to stabilize protein drugs, including buffers, salts, sugars, and surfactants. One of the roles of surfactants is to protect the protein drug from surface interactions that can destabilize the protein. Protein drug products formulated with surfactants usually contain either a polysorbate or poloxamer. Even in the presence of these surfactants, protein drug stability is often insufficient, particularly because of agitation-induced aggregation. FM1000 is one of a series of surfactants containing an alkyl chain, an amino acid, and a polyetheramine. The characterization of the dynamics of FM1000 at various water/hydrophobic interfaces was compared to Polysorbate 20, Polysorbate 80, and Poloxamer 188. FM1000 stabilizes an interface 1−2 orders of magnitude faster than all three of these surfactants, even in the presence of protein. The faster dynamics leads to improved stabilization of model protein biologic drugs IgG and abatacept against agitation-induced aggregation. These results provide mechanistic understanding of the key causes and drivers of protein aggregation.

Characterization of Polysorbate 80 by Liquid Chromatography-Mass Spectrometry to Understand Its Susceptibility to Degradation and Its Oxidative Degradation Pathway

“…2 PS20 and PS80 have demonstrated higher surface activity than therapeutic proteins such as IgG, and therefore, are capable of competitively blocking the container surface at equilibrium, and stabilizing protein against surface-induced denaturation. 3 Polysorbates are synthesized from sorbitol, fatty acid (FA), and ethylene oxide (EO) via reactions including sorbitol dehydration, FA esterification, and ethoxylation.…”

Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

“…Polymer excipients are inactive ingredients included in pill formulations that are frequently, but not exclusively, used to sequester small molecules and larger payloads through noncovalent interactions with active pharmaceutical ingredients (APIs), , proteins, − and polynucelotides . In oral, intravenous, or intramuscular administration, the polymer works with the active ingredients as a stabilizer, both on the shelf and in vivo.…”

Surfactant Impact on Interfacial Protein Aggregation and Utilization of Surface Tension to Predict Surfactant Requirements for Biological Formulations

“…Polysorbate 20 is able to reduce to surface tension kinetically faster and to a lower equilibrium concentration compared to PS80. 25,26 PS80 has a lower surface excess concentration above the critical micelle concentration that may be attributed to the reduced flexibility for packing associated with the unsaturated hydrophobe. 26 Given the dynamic interface during agitation, it can be that interfacial equilibrium is not achieved during the study.…”