2024-01-16 デラウェア大学 (UD)
◆研究はPeptides of the National Academy of Sciencesに報告され、表面との相互作用に焦点を当て、製品製造の失敗を減少させるための解決策を提供。研究では表面と分子の相互作用、ウゾ形成の予測方法、薬剤の棚寿命に関する洞察が明らかにされ、将来の研究では分子構造の変更により問題を解決する可能性が模索される。
<関連情報>
- https://www.udel.edu/udaily/2024/january/molecule-mechanics-in-diabetes-obesity-medications-norman-wagner/
- https://www.pnas.org/doi/10.1073/pnas.2305770121
アシル化ペプチド、セマグルチドの表面媒介による自然乳化 Surface-mediated spontaneous emulsification of the acylated peptide, semaglutide
Qi Li, Vasudev Tangry, David P. Allen, Kevin D. Seibert, Ken K. Qian, and Norman J. Wagner
Proceedings of the National Academy of Sciences Published:January 16, 2024
DOI:https://doi.org/10.1073/pnas.2305770121
Significance
We identify the fundamental mechanisms of an undesired instability known as “ouzo” formation in a class of therapeutics used for treating type 2 diabetes and obesity. Spontaneous emulsification in solutions of acylated peptides in the presence of hydrophobic surfaces is elucidated as a function of physico-chemical conditions and surface hydrophobicity as characterized by Hansen solubility parameters. Quantitative prediction of the colloidal size is demonstrated using the classical Rayleigh theory, while formation rates reduce to a master curve dependent on the surface hydrophobicity and stirring rate. We demonstrate that colloidal physics and molecular thermodynamics provide quantitative predictions of the colloidal droplet size and qualitatively rank formation rates, thereby improving our understanding of this important class of therapeutic molecules.
Abstract
Acylated peptides composed of glucagon-like peptide-1 receptor agonists modified with a fatty acid side chain are an important class of therapeutics for type 2 diabetes and obesity but are susceptible to an unusual physical instability in the presence of hydrophobic surfaces, i.e., spontaneous emulsification, also known as ouzo formation in practice. In this work, light scattering, small-angle X-ray scattering, and circular dichroism measurements are used to characterize the physical properties of the semaglutide colloidal phase, including size distribution, shape, secondary structure, internal structure, and internal composition, as a function of solution physico-chemical conditions. The existence and size of the colloids formed are successfully predicted by a classical Rayleigh model, which identifies the parameters controlling their size and formation. Colloid formation is found to be catalyzed by hydrophobic surfaces, and formation rates are modeled as an autocatalytic reaction, enabling the formation of a master curve for various surfaces that elucidates the mechanism. Surfaces differ due to differences in surface wettability, which can be correlated with Hansen solubility parameters. This work provides insights into this unusual colloidal phenomenon and guides the peptide synthesis process and drug product formulation in the pharmaceutical industry.
