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Design of the formulation for therapeutic proteins – How to improve stability of drugs during freezing and in the dried state

corresponding

ANDREA ARSICCIO, ROBERTO PISANO*
*Corresponding author 
Department of Applied Science and Technology, Politecnico di Torino, Torino, Italy

Abstract

In the present work, the design of an appropriate formulation for biopharmaceuticals is discussed. Some advice on the choice of suitable excipients will be provided, with a focus on the freezing and drying processes. The basic scientific background on the subject will be combined with the latest results obtained by means of Molecular Dynamics, a powerful computational approach for the investigation of molecular-scale phenomena. The commercial potential of these discoveries will be discussed, and some hints on the future possible research trends in this field will be provided, as well.


INTRODUCTION

Therapeutic proteins, or biopharmaceuticals, play a fundamental role in the treatment of an increasing number of diseases. However, the long-term preservation of protein-based drugs represents an issue for pharmaceutical companies, due to the low stability of protein molecules. Two techniques which are commonly used for increasing the shelf life of biopharmaceuticals are freezing and drying, sometimes combined in the lyophilisation process. It is well-known, however, that both freezing and drying produce stresses which may result in a significant loss of activity of biopharmaceuticals (1). During freezing, denaturation may arise as consequence of pH shifts (2), cryoconcentration, phase-separation (3), adsorption onto the ice-water interface (4) or the low temperature used (5). By contrast, removal of the hydration shell surrounding the protein surface is the main cause of protein unfolding in the dried state (6). It is therefore clear that an appropriate formulation must be added to prevent, or at least minimize, an undesired loss of activity. Bulk stabilization is generally provided by sugars, polyols or amino acids. Regardless of thei ...