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Krieg, Dennis; Svilenov, Hristo; Gitter, Julian H.; Winter, Gerhard (2020): Overcoming challenges in co-formulation of proteins with contradicting stability profiles - EPO plus G-CSF. In: European Journal of Pharmaceutical Sciences, Vol. 141, 105073
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Abstract

The co-formulation of drugs is widely used for small molecules, e.g. fixed-dose-combinations of synergistic medicines in the treatment of infections, diabetes or neurodegenerative diseases. For protein drugs, only a few studies have been published to elucidate the challenges of stabilizing two proteins in one formulation. Here, we show a systematic study with the model proteins EPO and G-CSF, which differ significantly in their physicochemical properties. We apply several analytical methods to investigate the stability of the co-formulated proteins in the liquid and solid state. Forced degradation studies at elevated temperature indicate poor stability of the liquid co-formulations. Therefore, we use lyophilization as a stabilization strategy. Finally, we adopt an elegant approach, in which the proteins are lyophilized at pH 4.0 and reconstituted with buffer at pH 7.0 to obtain high monomer recovery and to preserve the protein structure of both EPO and G-CSF. After reconstitution, both proteins in co-formulation remain stable for the timespan until eventual application in patients. With this case study, we demonstrate how to overcome some challenges during the co-formulation of therapeutic proteins.