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Characterization of Peptide-Preservative Interaction and Reversibility by NMR Spectroscopy
Dan Xie1, Sharon Sibley1, Luke W Arbogast1
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
Molecular Pharmaceutics
|October 15, 2025
Summary
Antimicrobial preservatives in incretin peptide formulations were investigated. Phenol interacted with the peptide, but effects were reversible and did not impact drug stability or bioactivity, supporting reformulated obesity medications.
Area of Science:
- Pharmaceutical Sciences
- Analytical Chemistry
- Biochemistry
Background:
- Incretin-based therapies are effective for weight loss but require accessible formulations.
- Reformulated multiple-dose preserved incretin peptide products may improve patient access and reduce costs.
- Understanding preservative-peptide interactions is vital for ensuring drug product efficacy.
Purpose of the Study:
- To investigate the interactions between a model therapeutic incretin peptide and common antimicrobial preservatives (benzyl alcohol, phenol).
- To assess the impact of these interactions on peptide stability and bioactivity.
- To evaluate the reversibility of preservative-induced spectral changes.
Main Methods:
- 1D and 2D Nuclear Magnetic Resonance (NMR) spectroscopy to study peptide-preservative interactions.
- High-Performance Liquid Chromatography (HPLC) to assess drug stability.
- Cell-based bioassays to determine peptide bioactivity.
- Preservative removal studies to assess reversibility.
Main Results:
- Benzyl alcohol showed no significant interaction with the model peptide.
- Phenol exhibited binding to the peptide, causing observable spectral perturbations.
- Preservative-induced spectral changes were fully reversible upon preservative removal.
- Despite phenol-peptide interaction, the stability and bioactivity of the peptide remained unchanged in the preserved formulation compared to the nonpreserved one.
Conclusions:
- Antimicrobial preservatives like benzyl alcohol and phenol can be used in incretin peptide formulations.
- Phenol's interaction with the peptide is reversible and does not compromise drug stability or bioactivity.
- These findings support the development of stable, effective, and accessible reformulated incretin-based obesity medications.
- Nonclinical data are crucial for de-risking future clinical bioequivalence studies for reformulated drug products.
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