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Deterioration of lyophilized pharmaceutical proteins
H R Costantino1, S P Schwendeman, R Langer
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. klibanov@mit.edu
Biochemistry. Biokhimiia
|June 4, 1998
Summary
Understanding protein instability in solid formulations is key. This review details aggregation mechanisms like thiol-disulfide exchange and beta-elimination, aiding the development of stable protein pharmaceuticals.
Area of Science:
- Biochemistry
- Pharmaceutical Sciences
- Materials Science
Background:
- Proteins are essential in pharmaceuticals but are fragile.
- Solid-state formulation enhances protein stability but can alter structure.
- Proteins in solid form face inactivation via aggregation and other degradation pathways.
Purpose of the Study:
- To review mechanisms of protein inactivation in solid formulations.
- To emphasize laboratory case studies on protein aggregation.
- To guide the rational design of stable solid protein products.
Main Methods:
- Review of protein aggregation mechanisms, including thiol-disulfide exchange and beta-elimination.
- Analysis of lyophilization-induced structural changes.
- Investigation of formaldehyde-mediated aggregation in formalinized vaccines.
Main Results:
- Proteins with disulfide bonds and free thiols aggregate via thiol-disulfide exchange, exacerbated by lyophilization.
- Proteins with disulfides but no free thiols can aggregate through beta-elimination of native disulfides.
- Formaldehyde can induce aggregation in specific protein formulations, such as formalinized vaccines.
Conclusions:
- Knowledge of protein deterioration pathways is crucial for developing stable solid formulations.
- Understanding aggregation mechanisms enables rational design of robust protein pharmaceuticals.
- Targeted strategies can mitigate degradation, improving the shelf-life and efficacy of protein-based products.