Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist

被引：365

作者：

Buckley, Stephen T. ^{[1
]}

Baekdal, Tine A. ^{[2
]}

Vegge, Andreas ^{[1
]}

Maarbjerg, Stine J. ^{[2
]}

Pyke, Charles ^{[1
]}

Ahnfelt-Ronne, Jonas ^{[1
]}

Madsen, Kim G. ^{[1
]}

Scheele, Susanne G. ^{[1
]}

Alanentalo, Tomas ^{[1
]}

Kirk, Rikke K. ^{[1
]}

Pedersen, Betty L. ^{[1
]}

Skyggebjerg, Rikke B. ^{[1
]}

Benie, Andrew J. ^{[1
]}

Strauss, Holger M. ^{[1
]}

Wahlund, Per-Olof ^{[1
]}

Bjerregaard, Simon ^{[1
]}

Farkas, Erzsebet ^{[3
]}

Fekete, Csaba ^{[3
,4
]}

Sondergaard, Flemming L. ^{[2
]}

Borregaard, Jeanett ^{[2
]}

Hartoft-Nielsen, Marie-Louise ^{[2
]}

Knudsen, Lotte Bjerre ^{[1
]}

机构：

[1] Novo Nord AS, DK-2760 Malov, Denmark

[2] Novo Nord AS, DK-2860 Soborg, Denmark

[3] Hungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, H-1083 Budapest, Hungary

[4] Tufts Med Ctr, Tupper Res Inst, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02111 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2018年 / 10卷 / 467期

关键词：

INTESTINAL PERMEATION ENHANCERS; GASTRIC-MUCOSA; ORAL DELIVERY; GLYCEMIC CONTROL; LIRAGLUTIDE; FORMULATION; SODIUM; IMPACT; ACID; DRUG;

D O I：

10.1126/scitranslmed.aar7047

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.

引用

页数：13

共 41 条

[1] Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials [J].