Protein stabilization by cyclodextrins in the liquid and dried state.

Abstract Aggregation is arguably the biggest challenge for the development of stable formulations and robust manufacturing processes of therapeutic proteins. In search of novel excipients inhibiting protein aggregation, cyclodextrins and their derivatives have been under examination for use in parenteral protein products since more than 20 years and significant research work has been accomplished highlighting the great potential of cyclodextrins as stabilizers of therapeutic proteins. Oftentimes, the potential of cyclodextrins to inhibit protein aggregation has been attributed to their capability to incorporate hydrophobic residues on aggregation-prone proteins or on their partially unfolded intermediates into the hydrophobic cavity. In addition, also other mechanisms besides or even instead of complex formation play a role in the stabilization mechanism, e.g. non-ionic surfactant-like effects. In this review a comprehensive overview of the available research work on the beneficial use of cyclodextrins and their derivatives in protein formulations, liquid as well as dried, is provided. The mechanisms of stabilization against different kinds of stress conditions, such as thermal or surface-induced, are discussed in detail.