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Salcaprozate-based ionic liquids for GLP-1 gastric delivery: A mechanistic understanding of in vivo performance. | LitMetric

AI Article Synopsis

Article Abstract

Oral delivery of peptides requires formulations with high concentrations of permeation enhancer (PE) to promote absorption, and often necessitates fasting time between dosing and food ingestion. Improved formulations promoting a more rapid absorption would increase convenience of use but requires a faster onset of action. We have developed a salcaprozate-based ionic liquid (IL) formulation, namely choline salcaprozate (CHONAC), for oral delivery of a glucagon-like peptide-1 (GLP-1) analogue via gastric absorption. In vitro studies confirmed the higher amount of PE accommodated in the same volume of dosage form as well as faster release of the active pharmaceutical ingredient (API) and PE compared to the tablet reference. Storage stability of the CHONAC formulation was demonstrated for up to 3 weeks at 4 °C. The peptide absorption efficacy of the IL formulation was first evaluated in vivo in rats and anesthetized dogs, showing a faster absorption compared to the reference formulations. In awake dogs, while the CHONAC formulation still enabled earlier API absorption, its overall exposure was inferior to the tablet reference. This was attributed mostly to the gastric physiology, causing formulation dilution in the presence of additional fluid as well as fast transit of liquids into the duodenum, where peptides liable to proteolytic degradation such as the one used in this study showed a negligible absorption, potentially also due to a lower permeation-enhancing capability of CHONAC in the duodenal region. Exploring these issues, an in vivo study in anesthetized dogs involving repeated dosing of a liquid salcaprozate-based formulation in the stomach revealed the potential to sustain peptide absorption throughout the dosing period with a constant absorption rate. In conclusion, combining the advantages of high PE amounts and fast onset of action provided by the IL formulation, and ensuring a prolonged interaction of peptide and PE at a relevant concentration with the stomach epithelium, are necessary to enhance oral peptide bioavailability via gastric delivery.

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Source
http://dx.doi.org/10.1016/j.jconrel.2024.11.036DOI Listing

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