Mechanism of Stabilization of Proteins by Poly-hydroxy Co-solvents: Concepts and Implications in Formulation Development

摘要

Polyols (aka polyhydroxy co-solvents aka osmolytes) such as sucrose have long been known to impart thermodynamic stability to proteins in solution. Recent advances in biotechnology and in the development of proteins for therapeutic applications has led to an increased interest in these neutral co-solvents (more than 60 % of mAb formulations currently in market have polyhydroxy alcohols as excipients). Despite widespread efforts (> 40 years), the exact mechanism of the modulation of the chemical potential of proteins by polyols is not well understood and hence as a consequence, scientists do not dare to evaluate co-solvents other than a few selected ones for use in protein formulations. Considering that co-solvents should have opposite effects on thermodynamic stability and solubility, and non ideality of high concentration protein solutions complicates the kinetic and/or thermodynamic stabilization effect provided by polyols, the choice of a suitable co-solvent for a formulation may not be straightforward. Present review is focused on analyzing the concepts developed over the years towards the mechanistic understanding of the impact of polyhydroxy co-solvents on the stability of proteins in solution including the discussion of the widely accepted theory of preferential exclusion. Additionally, the review details the present state of knowledge in regards to the correlations between the effects of co-solvents on the thermodynamic and kinetic stability of proteins. The overall goal is to summarize the key results and the prevalent theories such as to provide the protein formulator with a better understanding of the selection criterion for the cosolvent/s.