Reference
Kim, J. C., Park, E. J., & Na, D. H. (2022). Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals. Pharmaceuticals, 15(12), Article 12. https://doi.org/10.3390/ph15121585
Info
FirstAuthor:: Kim, Jae Cheon
Author:: Park, Eun Ji
Author:: Na, Dong Hee
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Title:: Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals
Year:: 2022
Citekey:: KimEtAl_2022_GastrointestinalPermeationEnhancers
itemType:: journalArticle
Journal:: Pharmaceuticals
Volume:: 15
Issue:: 12
Pages:: 1585
DOI:: 10.3390/ph15121585
Link
Abstract
Recently, two oral-administered peptide pharmaceuticals, semaglutide and octreotide, have been developed and are considered as a breakthrough in peptide and protein drug delivery system development. In 2019, the Food and Drug Administration (FDA) approved an oral dosage form of semaglutide developed by Novo Nordisk (Rybelsus®) for the treatment of type 2 diabetes. Subsequently, the octreotide capsule (Mycapssa®), developed through Chiasma’s Transient Permeation Enhancer (TPE) technology, also received FDA approval in 2020 for the treatment of acromegaly. These two oral peptide products have been a significant success; however, a major obstacle to their oral delivery remains the poor permeability of peptides through the intestinal epithelium. Therefore, gastrointestinal permeation enhancers are of great relevance for the development of subsequent oral peptide products. Sodium salcaprozate (SNAC) and sodium caprylate (C8) have been used as gastrointestinal permeation enhancers for semaglutide and octreotide, respectively. Herein, we briefly review two approved products, Rybelsus® and Mycapssa®, and discuss the permeation properties of SNAC and medium chain fatty acids, sodium caprate (C10) and C8, focusing on Eligen technology using SNAC, TPE technology using C8, and gastrointestinal permeation enhancement technology (GIPET) using C10.
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Rybelsus® was the first oral peptide drug based on the PE strategy and was approved by the FDA and EMA in September 2019 and March 2020, respectively. Rybelsus, indicated for type 2 diabetes mellitus (T2DM), is an oral formulation of semaglutide with sodium salcaprozate (SNAC) as the PE.
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The second contribution is the improvement of oral absorption by SNAC. Unlike SNAC’s mechanism presented by the existing EligenTM technology, Novo Nordisk asserts that SNAC increases the transcellular absorption of semaglutide by elevating the local pH around the tablet in the stomach
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protects against pepsin by increasing the pH near the semaglutide that is eluted after the tablet sinks near the lower mucous membrane of the stomach, improves the solubility of the semaglutide, and induces monomerization in the local environment [61]. According to Novo Nordisk, these PE mechanisms of SNAC work specifically for semaglutide [55].
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lsion from the membrane leaflet after insertion into the membrane was also greater [75]. There have been studies on SNAC, a representative material of EligenTM technologybased PEs, for the oral administration of insulin, octreotide, etc. (Table 4). This has led to the successful development of Rybelsus® (oral semaglutide). Most studies on the mechanism of SNAC have agreed that it acts as a transcellular PE (Table 5). Furthermore, many studies have concluded that SNAC does not exhibit surfactant-like action and membrane perturbation tendencies, as MCFA does. The representative mechanism of SNAC is the carrier mechanism. That is, SNAC
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They put forth that the PE mechanism of SNAC works specifically for semaglutide. They found that SNAC protects semaglutide from enzymatic degradation in the stomach during uptake by elevating the local pH, and equally increases the transcellular uptake of semaglutide by the mechanism of induction of monomerization of semaglutide and increase in membrane fluidity (Figure 6).
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they suggested that it is appropriate to target absorption in the stomach, as is the case with semaglutide, which must be co-formulated with a PE such as SNAC.