Stability of Drugs and Dosage Forms Sumie Yoshioka

5.3. • Degradation Kinetics of Peptide and Protein Pharmaceuticals 197
dextran, resulting in increased storage stability. 856 In contrast, addition of polyvinyl alcohol
with higher mobility lowered the T mc 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- β -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 I g M monoclonal antibody, 873 and human keratinocyte growth factor.
874,875
5.3. Degradation Kinetics of Peptide and Protein Pharmaceuticals
5.3.1. Quantitative Description of Peptide and Protein Degradation
Chemical degradation of peptide and protein pharmaceuticals can also be analyzed
kinetically in the same manner as for small-molecule drugs. Specifically, chemical degradation
of small peptides in aqueous solutions generally conforms to simple first-order kinetics.
For example, first-order kinetics have been reported for the hydrolysis in aqueous solution
of secretin, which has 27 amino acid residues (Fig. 205). 795 Deamidation, hydrolysis, and
epimerization of an LH-RH antagonist having 10 amino acid residues (Fig. 206), 802 deamidation
of calcitonin, having 32 amino acid residues (Fig. 207), 876 and degradation of
gonadorelin 877 and growth hormone-releasing hexapeptide 878 also follow first-order kinetics.
Kinetic analysis has even been attempted for the degradation of peptide and protein
pharmaceuticals for which the mechanism and pathways are unknown. Apparent inactivation
of α -chymotrypsin and bromelain in aqueous solutions was described by monoexponential
Figure 205. First-order plots of the hydrolysis of secretin in aqueous solution at varying pH values (60°C).
(Reproduced from Ref. 795 with permission.)