{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:04:09Z","timestamp":1789473849202,"version":"build-2803163510"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Drug Deliv."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Oral delivery of peptides is a promising alternative to invasive injectable therapies, offering improved patient adherence and convenience. Glucagon-like peptide-1 (GLP-1) analogs, in particular, are highly effective for the management of type 2 diabetes mellitus and obesity, yet their oral bioavailability remains limited by enzymatic degradation and poor intestinal permeability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we aimed to design a lipid-based formulation (LBF) of the model GLP-1 analog exenatide (EXE) in its hydrophobic ion-paired (HIP) form, incorporating permeation-enhancing excipients, and evaluate its performance in enteric capsule systems.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and discussion<\/jats:title>\n                    <jats:p>\n                      EXE-HIP was prepared with sodium docusate (1:4 molar ratio), which increased lipophilicity (log P = 0.9 \u00b1 0.2 vs. \u22122.9 \u00b1 0.3 for EXE) and markedly improved solubility in lipid excipients, especially in Labrafac\u2122 MC60, a known promoter of intestinal permeability. An optimized LBF composed of 85% Labrafac\u2122 MC60, 10% Kolliphor\u00ae RH40, and 5% propylene glycol was developed, with a final particle size of 106\u00a0nm, and it was loaded with 6\u00a0mg\/g solubilized EXE (HIP form) and 20\u00a0mg\/g of sodium caprate (complementary permeation enhancer). The formulation exhibited significant protection against\n                      <jats:monospace>\u03b1<\/jats:monospace>\n                      -chymotrypsin-mediated degradation, which is consistent with sequestration of EXE-HIP within lipid droplets that limit enzymatic access. Short-term stability studies highlighted formulation-dependent degradation behavior, with higher impurity formation observed for solubilized EXE-HIP than for suspended EXE acetate, particularly at room temperature. To further support oral delivery, customized gelatin\/HPMC-AS enteric capsules were engineered to provide a complementary two-tier protection strategy: (i) protecting the peptide and lipid phase from gastric enzymatic degradation and preventing premature dilution in gastric fluids that could displace the peptide from its protective lipid environment, while (ii) ensuring coordinated release of both EXE-HIP and the permeation enhancers at the intestinal absorption site. These capsules met the USP delayed release requirements. Overall, this work presents a promising proof-of-concept oral delivery platform that combines HIP chemistry, lipid-based formulation, and ready-to-use enteric capsule technology to enhance\n                      <jats:italic>in vitro<\/jats:italic>\n                      enzymatic protection of peptide therapeutics, thereby laying the groundwork for future studies to assess bioavailability and therapeutic efficacy\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fddev.2026.1770094","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:08:50Z","timestamp":1779430130000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A two-tier protection strategy for oral delivery of GLP-1 peptides: lipid-based formulation combined with enteric capsules"],"prefix":"10.3389","volume":"6","author":[{"given":"Camille","family":"Dumont","sequence":"first","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Klatt","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Picco","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Nombret","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Agisson","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euengla","family":"Uku","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibault","family":"Saurel","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Jannin","sequence":"additional","affiliation":[{"name":"Capsugel France SAS","place":["Colmar, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0276814","DOI":"10.1371\/journal.pone.0276814","article-title":"Prevalence, causes, impacts, and management of needle phobia: an international survey of a general adult population","volume":"17","author":"Alsbrooks","year":"2022","journal-title":"PLOS ONE"},{"key":"B2","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jconrel.2018.01.012","article-title":"Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs","volume":"273","author":"Bonengel","year":"2018","journal-title":"J. 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