Egbu, R;
van der Walle, C;
Brocchini, S;
Williams, GR;
(2020)
Inhibiting the fibrillation of a GLP-1-like peptide.
International Journal of Pharmaceutics
, 574
, Article 118923. 10.1016/j.ijpharm.2019.118923.
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Williams IJP-D-19-01906 accepted MS.pdf - Accepted Version Download (1MB) | Preview |
Abstract
Aggregation, including the formation of fibrils, poses significant challenges for the development of therapeutic peptides. To develop stable peptide formulations, some understanding of the mechanisms underpinning the fibrillation process is required. A thioflavin T fluorescence assay was first used to determine the fibrillation profile of a GLP-1-like peptide (G48) at conditions being considered to formulate the peptide. G48 concentrations ranged from 0 – 600 µM and three pH values (pH 3.7, 7.4 and 8.5) were evaluated. Kinetic data demonstrate that G48 displays a pH-dependent aggregation profile. At pH 3.7, which is below the isoelectric point of G48 (pI ∼ 5), kinetics representative of amorphous aggregates forming via a nucleation-independent mechanism were seen. At pH 7.4 and 8.5 (pH > pI) typical nucleation-dependent aggregation kinetics were observed. The weight concentration of β-sheet rich aggregates (FLmax) correlated inversely with net charge, so lower FLmax values were observed at pH 3.7 and 8.5 than at pH 7.4. Incorporation of a non-ionic surfactant (polysorbate 80) into the peptide solution suppressed the fibrillation of G48 at all pH values and maintained the native peptide conformation, whereas a phenolic co-formulant (ferulic acid) had minimal effects on fibril growth. Peptide fibrillation, which can occur within a range of formulation concentrations and pH values, can hence be inhibited by the judicious use of excipients.
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