Monoacyl phospholipids to replace polysorbates as interfacial stabilizers in parenteral monoclonal antibody...

Protein-based drugs are prone to both physical and chemical instability in aqueous solutions. Surfactants, such as polysorbates (PS), are commonly employed to mitigate interfacial stress, thus preventing protein aggregation and particle formation. However, polysorbates can undergo enzymatic hydrolysis by residual host cell proteins and oxidation during long-term storage in parenteral formulations. This can lead to the generation of free fatty acid particles, inadequate protein stabilization, and protein oxidation. In this study, we investigated several monoacyl phospholipids (MAPLs) with varying fatty acid chains as potential alternative surfactants for monoclonal antibody (mAb) formulations and compared their efficacy to the industry standard, polysorbate 80. The hemolytic activity of MAPLs was tested using erythrocytes in 95 % plasma. All MAPLs prevented mAb particle formation during shaking and freezing-thawing at surfactant concentrations several orders of magnitude below the threshold for hemolysis, suggesting that the risk of erythrocyte damage from MAPLs is non-critical. Stabilization of mAbs occurred around the critical micelle concentration, which were comparable to that of PS80, but MAPLs achieved lower interfacial tension values. MAPLs were found to be more resistant to enzymatic hydrolysis by porcine liver esterase and forced oxidation than PS80. After long-term liquid storage, lyso-myristoyl-phosphatidylcholine (LPC 14:0) at low concentrations provided superior mAb stabilization to PS80, which exhibited substantial chemical degradation. At higher concentrations, both PS80 and LPC 14:0 showed a decrease in surfactant concentration. Lyophilization enhanced mAb stabilization relative to liquid formulations, with MAPLs performing as well as PS80 at high concentrations and outperforming PS80 at low concentrations. MAPLs also better preserve the siliconization in pre-filled syringe (PFS) barrels compared to PS80. In short, MAPLs demonstrate mAb stabilization and chemical stability comparable to, and in some cases superior to, PS80, making them a promising alternative as interfacial stabilizers in parenteral protein formulations and warranting further exploration.