{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:23:52Z","timestamp":1791404632842,"version":"4.3.3"},"reference-count":103,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2013,3,1]],"date-time":"2013-03-01T00:00:00Z","timestamp":1362096000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Diabetes Sci Technol"],"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:p>Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: Higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The main barriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized.<\/jats:p>","DOI":"10.1177\/193229681300700228","type":"journal-article","created":{"date-parts":[[2014,1,10]],"date-time":"2014-01-10T10:36:05Z","timestamp":1389350165000},"page":"520-531","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":192,"title":["Oral Insulin Delivery: How Far are We?"],"prefix":"10.1177","volume":"7","author":[{"given":"Pedro","family":"Fonte","sequence":"first","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade (CICS), Instituto Superior de Ci\u00eancias da Sa\u00fade\u2014Norte, CESPU, Gandra, Portugal"},{"name":"REQUIMTE, Department of Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade (CICS), Instituto Superior de Ci\u00eancias da Sa\u00fade\u2014Norte, CESPU, Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salette","family":"Reis","sequence":"additional","affiliation":[{"name":"REQUIMTE, Department of Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sarmento","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade (CICS), Instituto Superior de Ci\u00eancias da Sa\u00fade\u2014Norte, CESPU, Gandra, Portugal"},{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal"},{"name":"INEB\u2014Institute for Biomedical Engineering, University of Porto, Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2013,3,1]]},"reference":[{"key":"bibr1-193229681300700228","doi-asserted-by":"publisher","DOI":"10.12968\/bjon.2007.16.16.27079"},{"key":"bibr2-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199307293290502"},{"key":"bibr3-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199309303291401"},{"key":"bibr4-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1001\/jama.287.19.2563"},{"key":"bibr5-193229681300700228","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-144-7-200604040-00005"},{"key":"bibr6-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1177\/193229680900300323"},{"key":"bibr7-193229681300700228","first-page":"229","volume-title":"Pharmaceutical biotechnology","author":"Beals JM","year":"1997"},{"key":"bibr8-193229681300700228","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199733040-00004"},{"key":"bibr9-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1038\/nrd836"},{"key":"bibr10-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2007.08.019"},{"key":"bibr11-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(98)00075-1"},{"key":"bibr12-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-1241.2010.02577.x"},{"key":"bibr13-193229681300700228","doi-asserted-by":"publisher","DOI":"10.3109\/10611860903302815"},{"key":"bibr14-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.08.087"},{"key":"bibr15-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2003.12.017"},{"key":"bibr16-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1208\/pt030433"},{"key":"bibr17-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2005.09.028"},{"key":"bibr18-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5173(02)00024-8"},{"key":"bibr19-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2004.04.013"},{"key":"bibr20-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2007.06.052"},{"key":"bibr21-193229681300700228","unstructured":"Diabetology. http:\/\/www.diabetology.co.uk\/. Accessed January 21, 2012."},{"key":"bibr22-193229681300700228","unstructured":"Oramed Pharmaceuticals. http:\/\/www.oramed.com\/. Accessed January 22, 2012."},{"key":"bibr23-193229681300700228","unstructured":"BOWS Pharmaceuticals AG. http:\/\/www.bowspharma.com\/. Accessed January 22, 2012."},{"key":"bibr24-193229681300700228","unstructured":"Emisphere Technologies. http:\/\/www.emisphere.com\/. Accessed January 22, 2012."},{"key":"bibr25-193229681300700228","unstructured":"Novo Nordisk. http:\/\/www.novonordisk.com\/. Accessed January 22, 2012."},{"key":"bibr26-193229681300700228","unstructured":"Merrion Pharmaceuticals. http:\/\/www.merrionpharma.com\/. Accessed January 21, 2012."},{"key":"bibr27-193229681300700228","unstructured":"Biocon Biopharmaceuticals. http:\/\/www.biocon.com\/. Accessed January 21, 2012."},{"key":"bibr28-193229681300700228","unstructured":"Diasome Pharmaceuticals. http:\/\/www.diasome.com\/. Accessed January 21, 2012."},{"key":"bibr29-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1177\/193229680900300627"},{"key":"bibr30-193229681300700228","unstructured":"Biolaxy. http:\/\/www.biolaxy.com\/. Accessed January 21, 2012."},{"key":"bibr31-193229681300700228","unstructured":"Access Pharmaceuticals. http:\/\/www.accesspharma.com. Accessed January 22, 2012."},{"key":"bibr32-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2009.01146.x"},{"key":"bibr33-193229681300700228","unstructured":"Kidron M, Eldor R, Miteva Y, Freier R, Arbit E. Extended exposure to an oral insulin formulation yields decreased insulin secretion in type II diabetes subjects. Presented at the Diabetes Technology Meeting, Bethesda, MD, November 11\u201313, 2010."},{"key":"bibr34-193229681300700228","unstructured":"Eldor R, Arbit E, Miteva Y, Freier R, Kidron M. Oral insulin: Type I diabetes (T1DM) patient response upon preprandial administration. Presented at the 70th American Diabetes Association Scientific Sessions, Orlando, FL, June 25\u201329, 2010."},{"key":"bibr35-193229681300700228","unstructured":"Eldor R, Arbit E, Miteva Y, Kidron M. Evaluation of the safety and efficacy of two oral insulin formulations in healthy volunteers. Presented at the Diabetes Technology Meeting, San Francisco, CA, October 2011."},{"key":"bibr36-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018888927852"},{"key":"bibr37-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0939-6411(00)00087-4"},{"key":"bibr38-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(01)00105-3"},{"key":"bibr39-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0927-7765(02)00053-X"},{"issue":"4","key":"bibr40-193229681300700228","first-page":"743","volume":"2","author":"Sarmento B","year":"2007","journal-title":"Int J Nanomedicine."},{"key":"bibr41-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2006.07.026"},{"key":"bibr42-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(76)80016-6"},{"issue":"4","key":"bibr43-193229681300700228","first-page":"246","volume":"38","author":"Axt J","year":"1983","journal-title":"Pharmazie."},{"key":"bibr44-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5173(97)00237-8"},{"key":"bibr45-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5173(01)00579-8"},{"issue":"6","key":"bibr46-193229681300700228","first-page":"983","volume":"16","author":"Das N","year":"1988","journal-title":"Biochem Int."},{"key":"bibr47-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.42.1954"},{"key":"bibr48-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016009313548"},{"key":"bibr49-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(00)00120-4"},{"key":"bibr50-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-3659(02)00411-X"},{"key":"bibr51-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1166\/jnn.2006.416"},{"key":"bibr52-193229681300700228","doi-asserted-by":"publisher","DOI":"10.2337\/diab.37.2.246"},{"issue":"11","key":"bibr53-193229681300700228","first-page":"1051","volume":"23","author":"Pan Y","year":"2002","journal-title":"Acta Pharmacol Sin."},{"key":"bibr54-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(00)00123-X"},{"key":"bibr55-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5173(02)00486-6"},{"key":"bibr56-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9367-4"},{"key":"bibr57-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1021\/bm0607776"},{"key":"bibr58-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2010.12.007"},{"key":"bibr59-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2004.03.023"},{"key":"bibr60-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1021\/bm060065f"},{"key":"bibr61-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012106907708"},{"key":"bibr62-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2007.12.037"},{"key":"bibr63-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2009.01.011"},{"key":"bibr64-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2006.12.007"},{"key":"bibr65-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2010.04.006"},{"key":"bibr66-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1021\/bm0703923"},{"key":"bibr67-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.12.003"},{"key":"bibr68-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2007.05.019"},{"key":"bibr69-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1002\/9780470688397.ch11"},{"key":"bibr70-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-3659(00)00339-4"},{"key":"bibr71-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.08.013"},{"key":"bibr72-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(02)00228-4"},{"key":"bibr73-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2007.09.013"},{"key":"bibr74-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1163\/1568562041753098"},{"key":"bibr75-193229681300700228","unstructured":"Alonso-Sande M, Delgado A, Evora C, Zoniou M, Remu\u00f1\u00e1n-L\u00f3pez C, Alonso MJ, PLGA-mannosamine nanoparticles as new carriers for oral immunization. 2nd NanoSpain Workshop, Barcelona, Spain, March 14\u201317, 2005."},{"key":"bibr76-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20750"},{"key":"bibr77-193229681300700228","doi-asserted-by":"publisher","DOI":"10.3109\/02652040903515490"},{"key":"bibr78-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2007.04.004"},{"key":"bibr79-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.10.023"},{"key":"bibr80-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1021\/bm700916h"},{"key":"bibr81-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(03)00041-3"},{"issue":"1","key":"bibr82-193229681300700228","first-page":"57","volume":"40","author":"Hou ZQ","year":"2005","journal-title":"Yao Xue Xue Bao."},{"key":"bibr83-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0939-6411(03)00145-0"},{"key":"bibr84-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2006.06.019"},{"key":"bibr85-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/S0939-6411(00)00084-9"},{"key":"bibr86-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1517\/17425247.5.1.45"},{"key":"bibr87-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1007\/s13346-011-0023-5"},{"key":"bibr88-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1081\/DDC-200047802"},{"key":"bibr89-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.b.31241"},{"key":"bibr90-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2010.08.009"},{"key":"bibr91-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2012.01.002"},{"key":"bibr92-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2006.04.014"},{"key":"bibr93-193229681300700228","doi-asserted-by":"publisher","DOI":"10.3109\/10717544.2010.522611"},{"key":"bibr94-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1166\/jnn.2006.445"},{"key":"bibr95-193229681300700228","doi-asserted-by":"publisher","DOI":"10.4155\/tde.10.109"},{"key":"bibr96-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1080\/10611860410001693706"},{"key":"bibr97-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1067"},{"key":"bibr98-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1007\/BF02867128"},{"key":"bibr99-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2007.05.250"},{"key":"bibr100-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1080\/17435390802398309"},{"key":"bibr101-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2008.12.066"},{"key":"bibr102-193229681300700228","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.06.055"},{"key":"bibr103-193229681300700228","first-page":"1005","volume":"45","author":"Zheng AP","year":"2010","journal-title":"Chin Pharm J."}],"container-title":["Journal of Diabetes Science and Technology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/193229681300700228","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/193229681300700228","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T18:10:02Z","timestamp":1777399802000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/193229681300700228"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3]]},"references-count":103,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2013,3]]}},"alternative-id":["10.1177\/193229681300700228"],"URL":"https:\/\/doi.org\/10.1177\/193229681300700228","relation":{},"ISSN":["1932-2968","1932-2968"],"issn-type":[{"value":"1932-2968","type":"print"},{"value":"1932-2968","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3]]}}}