APPROACHES FOR INCREASING THE SOLUTION STABILITY OF PROTEINS

Stabilization of proteins through proper formulation is an important c hallenge for the pharmaceutical industry. Two approaches for stabiliza tion of proteins in solution are discussed. First, work describing the effect of additives on the thermally induced denaturation and aggrega tion of low molecular weight urokinase is presented. The effects of th ese additives can be explained by preferential exclusion of the solute from the protein, leading to increased thermal stability with respect to denaturation. Diminished denaturation leads to reduced levels of a ggregation. The second approach involves stoichiometric replacement of polar counter ions (e.g., chloride, acetate, etc.) with anionic deter gents, in a process termed hydrophobic ion pairing (HIP). The HIP comp lexes of proteins have increased solubility in organic solvents. In th ese organic solvents, where the water content is limited, the thermal denaturation temperatures greatly exceed those observed in aqueous sol ution. In addition, it is possible to use HIP to selectively precipita te basic proteins from formulations that contain large amounts of stab ilizers, such as human serum albumin (HSA), with a selectivity greater than 2000-fold. This has been demonstrated for various mixtures of HS A and interleukin-4. (C) 1995 John Wiley & Sons, Inc.