Drug Product, Fill-Finish & Formulations
A Novel Excipient for High-Concentration Protein Formulations
High-concentration biologic formulations are challenging to develop due to a dramatic increase in solution viscosity at elevated protein concentration. The large viscosity is driven by attractive protein-protein interactions (PPIs), which promote long-lived clusters and networks in solution. Several formulation strategies exist to mitigate these attractive PPIs including adjusting the solution pH, ionic strength, and adding arginine. However, these strategies are limited and do not work for every molecule. Unfortunately, alternative solutions are lacking. Here we will disclose a novel excipient that lowers the viscosity of high-concentration biologics formulations. The decrease in viscosity is associated with a decrease in attractive PPIs, as measured by dynamic light scattering. Rigid-body docking simulations indicate that the excipient preferentially binds positively charged residues, such as arginine, and aromatic hydrophobic residues, such as tyrosine and phenylalanine, suggesting the dominant interaction mechanisms are π-cation interactions and π-π stacking interactions, respectively. Moreover, we show that typical additives, such as NaCl and arginine are ineffective in lowering the solution viscosity. Most importantly, the toxicology and pharmacokinetics/dynamics of the excipient are well-established, facilitating its use in biologics formulations from a regulatory stand point.