The Role of Excipients

Excipients used in peptide and protein formulations have major effects on denaturation and aggregation during storage. Freeze-dried proteins are most stable in viscous glassy states,858 and their stability is increased by interactions such as hydrogen bonding between proteins and surrounding molecules.859 Therefore, excipients that contribute to the maintenance of a glassy state or interact with the proteins can stabilize the proteins. Storage stability of alkaline phosphatase,860 recombinant tumor necrosis factor-a,814 a monoclonal antibody,861 and a recombinant human interleukin-1 receptor antagoist862 was increased by excipients such as sugars and HP-P-CD. Freeze-dried P-galactosidase was stabilized against inactivation during storage by adding excipients, which remained in an amorphous state.863,864

The glass transition temperature (Tg is considered to be a critical variable in estimating the molecular mobility of amorphous materials, and the addition of excipients with a high Ts is believed to increase the storage stability of lyophilized formulations. Stabilization by excipients that have high Tg values has been demonstrated with lyophilized bovine somatotropin and lysozyme865 and with lyophilized interleukin-2.866 The NMR relaxation-based critical mobility temperature ( Tmc), described above, can also be used as a measure of storage stability of lyophilized protein formulations. The TiC of a lyophilized bovine serum y-globu-lin formulation containing dextran increased with increasing molecular weight of the dextran, resulting in increased storage stability.856 In contrast, addition of polyvinyl alcohol with higher mobility lowered the Tmc of the formulation, resulting in decreased storage stability.857

The stability of proteins in aqueous solutions is improved by excipients exhibiting preferential exclusion, such as sugars.867 868 Porcine growth hormone was stabilized by

HP-P-CD.869 Denaturation during storage of urease and interleukin-2 was inhibited by nonionic surfactants such as poloxamers.870 Inhibition of protein aggregation in solutions by various sugars and surfactants has also been reported for acidic fibroblast growth factor.871

Stabilizing effects of polymeric additives have been reported for low-molecular-weight urokinase,872 human IgM monoclonal antibody,873 and human keratinocyte growth factor 874,875

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