{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:23:10Z","timestamp":1791404590886,"version":"4.3.3"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The aim of this work was to investigate alternative safe and effective permeation enhancers for buccal peptide delivery. Basic amino acids improved insulin solubility in water while 200 and 400\u2009\u03bcg\/mL lysine significantly increased insulin solubility in HBSS. Permeability data showed a significant improvement in insulin permeation especially for 10\u2009\u03bcg\/mL of lysine (p\u2009&lt;\u20090.05) and 10\u2009\u03bcg\/mL histidine (p\u2009&lt;\u20090.001), 100\u2009\u03bcg\/mL of glutamic acid (p\u2009&lt;\u20090.05) and 200\u2009\u03bcg\/mL of glutamic acid and aspartic acid (p\u2009&lt;\u20090.001) without affecting cell integrity; in contrast to sodium deoxycholate which enhanced insulin permeability but was toxic to the cells. It was hypothesized that both amino acids and insulin were ionised at buccal cavity pH and able to form stable ion pairs which penetrated the cells as one entity; while possibly triggering amino acid nutrient transporters on cell surfaces. Evidence of these transport mechanisms was seen with reduction of insulin transport at suboptimal temperatures as well as with basal-to-apical vectoral transport, and confocal imaging of transcellular insulin transport. These results obtained for insulin are the first indication of a possible amino acid mediated transport of insulin via formation of insulin-amino acid neutral complexes by the ion pairing mechanism.<\/jats:p>","DOI":"10.1038\/srep32498","type":"journal-article","created":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T10:49:59Z","timestamp":1472726999000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Pre-formulation and systematic evaluation of amino acid assisted permeability of insulin across in vitro buccal cell layers"],"prefix":"10.1038","volume":"6","author":[{"given":"Affiong","family":"Iyire","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Alaayedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afzal R.","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"BFsrep32498_CR1","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1046\/j.1464-5491.2003.01076.x","volume":"20","author":"DR Owens","year":"2003","unstructured":"Owens, D. R., Zinman, B. & Bolli, G. Alternative routes of insulin delivery. Diabetic Med. 20, 886\u2013898 (2003).","journal-title":"Diabetic Med"},{"key":"BFsrep32498_CR2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/S0939-6411(00)00144-2","volume":"51","author":"F Veuillez","year":"2001","unstructured":"Veuillez, F., Kalia, Y. N., Jacques, Y., Deshusses, J. & Buri, P. Factors and strategies for improving buccal absorption of peptides. Eur. J. Pharm. Biopharm. 51, 93\u2013109, doi: 10.1016\/S0939-6411(00)00144-2 (2001).","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"BFsrep32498_CR3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0168-3659(97)00259-9","volume":"53","author":"SJ Milstein","year":"1998","unstructured":"Milstein, S. J. et al. Partially unfolded proteins efficiently penetrate cell membranes\u2014implications for oral drug delivery. J. Controlled Release 53, 259\u2013267 (1998).","journal-title":"J. Controlled Release"},{"key":"BFsrep32498_CR4","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ejps.2013.04.025","volume":"49","author":"N Samiei","year":"2013","unstructured":"Samiei, N. et al. Ion-pair strategy for enabling amifostine oral absorption: rat in situ and in vivo experiments. Eur. J. Pharm. Sci. 49, 499\u2013504 (2013).","journal-title":"Eur. J. Pharm. Sci."},{"key":"BFsrep32498_CR5","unstructured":"Miller, J. M. The impact of molecular complexation on intestinal membrane permeation. The University of Michigan (2009)."},{"key":"BFsrep32498_CR6","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1002\/jps.21952","volume":"99","author":"JN Hemenway","year":"2010","unstructured":"Hemenway, J. N. et al. Preparation and physicochemical characterization of a novel water\u2010soluble prodrug of carbamazepine. J. Pharm. Sci. 99, 1810\u20131825 (2010).","journal-title":"J. Pharm. Sci."},{"key":"BFsrep32498_CR7","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2174\/156720111795767924","volume":"8","author":"A ElShaer","year":"2011","unstructured":"ElShaer, A., Khan, S., Perumal, D., Hanson, P. & R Mohammed, A. Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin. Curr. Drug Deliv. 8, 363\u2013372 (2011).","journal-title":"Curr. Drug Deliv"},{"key":"BFsrep32498_CR8","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1002\/jps.21663","volume":"98","author":"VD Ivaturi","year":"2009","unstructured":"Ivaturi, V. D. & Kim, S. K. Enhanced permeation of methotrexate in vitro by ion pair formation with L\u2010arginine. J. Pharm. Sci. 98, 3633\u20133639 (2009).","journal-title":"J. Pharm. Sci."},{"key":"BFsrep32498_CR9","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ejps.2013.10.002","volume":"51","author":"N Samiei","year":"2014","unstructured":"Samiei, N., Shafaati, A., Zarghi, A., Moghimi, H. & Foroutan, S. Enhancement and in vitro evaluation of amifostine permeation through artificial membrane (PAMPA) via ion pairing approach and mechanistic selection of its optimal counter ion. Eur. J Pharm. Sci. 51, 218\u2013223 (2014).","journal-title":"Eur. J Pharm. Sci."},{"key":"BFsrep32498_CR10","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1021\/js9900708","volume":"88","author":"BL Chen","year":"1999","unstructured":"Chen, B. L., Wu, X., Babuka, S. J. & Hora, M. Solubility of recombinant human tissue factor pathway inhibitor. J. Pharm. Sci. 88, 881\u2013888 (1999).","journal-title":"J. Pharm. Sci."},{"key":"BFsrep32498_CR11","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ejps.2014.05.022","volume":"62","author":"A ElShaer","year":"2014","unstructured":"ElShaer, A., Hanson, P. & R Mohammed, A. A novel concentration dependent amino acid ion pair strategy to mediate drug permeation using indomethacin as a model insoluble drug. Eur J. Pharm. Sci. 62, 124\u2013131 (2014).","journal-title":"Eur J. Pharm. Sci."},{"key":"BFsrep32498_CR12","unstructured":"Ohshima, H. & Makino, K. Colloid and Interface Science in Pharmaceutical Research and Development. (Elsevier, 2014)."},{"key":"BFsrep32498_CR13","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1021\/Ja00057a006","volume":"115","author":"J Matsuura","year":"1993","unstructured":"Matsuura, J., Powers, M. E., Manning, M. C. & Shefter, E. Structure and Stability of Insulin Dissolved in 1-Octanol. J. Am. Chem. Soc. 115, 1261\u20131264, doi: 10.1021\/Ja00057a006 (1993).","journal-title":"J. Am. Chem. Soc."},{"key":"BFsrep32498_CR14","unstructured":"Hames, D. & Hooper, N. Biochemistry, 3 th. New York, Taylor and Francis (2005)."},{"key":"BFsrep32498_CR15","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.jpba.2005.10.016","volume":"41","author":"X Xu","year":"2006","unstructured":"Xu, X., Fu, Y., Hu, H., Duan, Y. & Zhang, Z. Quantitative determination of insulin entrapment efficiency in triblock copolymeric nanoparticles by high-performance liquid chromatography. J. Pharm. Bio. Analysis 41, 266\u2013273, doi: 10.1016\/j.jpba.2005.10.016 (2006).","journal-title":"J. Pharm. Bio. Analysis"},{"key":"BFsrep32498_CR16","unstructured":"British Pharmacopoeia Vol. 1. London. The British Pharmacopoeia Commission (2012)."},{"key":"BFsrep32498_CR17","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0021-9258(18)43062-1","volume":"164","author":"J Lens","year":"1946","unstructured":"Lens, J. The solubility curve and the purity of insulin. J. Biol. Chem. 164, 223\u2013231 (1946).","journal-title":"J. Biol. Chem"},{"key":"BFsrep32498_CR18","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1016\/j.bpj.2012.01.060","volume":"102","author":"RM Kramer","year":"2012","unstructured":"Kramer, R. M., Shende, V. R., Motl, N., Pace, C. N. & Scholtz, J. M. Toward a molecular understanding of protein solubility: increased negative surface charge correlates with increased solubility. Biophys. J. 102, 1907\u20131915 (2012).","journal-title":"Biophys. J."},{"key":"BFsrep32498_CR19","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1111\/febs.12045","volume":"279","author":"M Landreh","year":"2012","unstructured":"Landreh, M. et al. Insulin solubility transitions by pH\u2010dependent interactions with proinsulin C\u2010peptide. FEBS J. 279, 4589\u20134597 (2012).","journal-title":"FEBS J"},{"key":"BFsrep32498_CR20","doi-asserted-by":"crossref","first-page":"4155","DOI":"10.1002\/jps.21327","volume":"97","author":"SR Trevino","year":"2008","unstructured":"Trevino, S. R., Scholtz, J. M. & Pace, C. N. Measuring and increasing protein solubility. J. Pharm. Sci. 97, 4155\u20134166 (2008).","journal-title":"J. Pharm. Sci."},{"key":"BFsrep32498_CR21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3109\/01480545.2011.589848","volume":"35","author":"X-y Xue","year":"2012","unstructured":"Xue, X.-y. et al. Promoting effects of chemical permeation enhancers on insulin permeation across TR146 cell model of buccal epithelium in vitro . Drug Chem. Toxicol. 35, 199\u2013207 (2012).","journal-title":"Drug Chem. Toxicol."},{"key":"BFsrep32498_CR22","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.1016\/j.biomaterials.2009.06.055","volume":"30","author":"L Yin","year":"2009","unstructured":"Yin, L. et al. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials 30, 5691\u20135700 (2009).","journal-title":"Biomaterials"},{"key":"BFsrep32498_CR23","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/S0021-9258(18)76023-7","volume":"99","author":"O Wintersteiner","year":"1933","unstructured":"Wintersteiner, O. & Abramson, H. A. The isoelectric point of insulin electrical properties of adsorbed and crystalline insulin. J. Biol. Chem. 99, 741\u2013753 (1933).","journal-title":"J. Biol. Chem."},{"key":"BFsrep32498_CR24","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1211\/0022357991776976","volume":"51","author":"T Uchiyama","year":"1999","unstructured":"Uchiyama, T. et al. Enhanced Permeability of Insulin across the Rat Intestinal Membrane by Various Absorption Enhancers: Their Intestinal Mucosal Toxicity and Absorption\u2010enhancing Mechanism of n\u2010Lauryl\u2010\u03b2\u2010D\u2010maltopyranoside. J. Pharm. Pharmacol. 51, 1241\u20131250 (1999).","journal-title":"J. Pharm. Pharmacol"},{"key":"BFsrep32498_CR25","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1023\/B:PHAR.0000026823.82950.ff","volume":"26","author":"S T\u00fcrker","year":"2004","unstructured":"T\u00fcrker, S., Onur, E. & \u00d3zer, Y. Nasal route and drug delivery systems. Pharm. World Sci. 26, 137\u2013142 (2004).","journal-title":"Pharm. World Sci."},{"key":"BFsrep32498_CR26","first-page":"25","volume":"263","author":"A Yamamoto","year":"1992","unstructured":"Yamamoto, A., Hayakawa, E., Kato, Y., Nishiura, A. & Lee, V. A mechanistic study on enhancement of rectal permeability to insulin in the albino rabbit. J. Pharm. Exp. Ther. 263, 25\u201331 (1992).","journal-title":"J. Pharm. Exp. Ther"},{"key":"BFsrep32498_CR27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0378-5173(92)90142-O","volume":"85","author":"R Gandhi","year":"1992","unstructured":"Gandhi, R. & Robinson, J. Mechanisms of penetration enhancement for transbuccal delivery of salicylic acid. Int J Pharm 85, 129\u2013140 (1992).","journal-title":"Int J Pharm"},{"key":"BFsrep32498_CR28","first-page":"1001","volume":"30","author":"AM Rotunda","year":"2004","unstructured":"Rotunda, A. M., Suzuki, H., Moy, R. L. & Kolodney, M. S. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol. Surg. 30, 1001\u20131008 (2004).","journal-title":"Dermatol. Surg"},{"key":"BFsrep32498_CR29","first-page":"3049","volume":"6","author":"S Sun","year":"2011","unstructured":"Sun, S., Liang, N., Kawashima, Y., Xia, D. & Cui, F. Hydrophobic ion pairing of an insulin-sodium deoxycholate complex for oral delivery of insulin. Int. J. Nanomed. 6, 3049 (2011).","journal-title":"Int. J. Nanomed"},{"key":"BFsrep32498_CR30","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1023\/A:1012076022420","volume":"14","author":"D Quintanar-Guerrero","year":"1997","unstructured":"Quintanar-Guerrero, D., All\u00e9mann, E., Fessi, H. & Doelker, E. Applications of the ion-pair concept to hydrophilic substances with special emphasis on peptides. Pharm. Res. 14, 119\u2013127 (1997).","journal-title":"Pharm. Res"},{"key":"BFsrep32498_CR31","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1152\/physrev.00018.2006","volume":"88","author":"S Br\u00f6er","year":"2008","unstructured":"Br\u00f6er, S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol. Rev. 88, 249\u2013286 (2008).","journal-title":"Physiol. Rev."},{"key":"BFsrep32498_CR32","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1208\/s12248-012-9337-6","volume":"14","author":"A Dahan","year":"2012","unstructured":"Dahan, A. & Miller, J. M. The solubility\u2013permeability interplay and its implications in formulation design and development for poorly soluble drugs. The AAPS Journal 14, 244\u2013251 (2012).","journal-title":"The AAPS Journal"},{"key":"BFsrep32498_CR33","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0928-0987(02)00083-0","volume":"16","author":"HM Nielsen","year":"2002","unstructured":"Nielsen, H. M. & Rassing, M. R. Nicotine permeability across the buccal TR146 cell culture model and porcine buccal mucosa in vitro: effect of pH and concentration. Eur. J. Pharm. Sci. 16, 151\u2013157 (2002).","journal-title":"Eur. J. Pharm. Sci."},{"key":"BFsrep32498_CR34","doi-asserted-by":"crossref","unstructured":"van Meerloo, J., Kaspers, G. J. & Cloos, J. In Cancer Cell Culture 237\u2013245 (Springer, 2011).","DOI":"10.1007\/978-1-61779-080-5_20"},{"key":"BFsrep32498_CR35","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0378-5173(96)04640-6","volume":"141","author":"J Jacobsen","year":"1996","unstructured":"Jacobsen, J., Pedersen, M. & Rassing, M. R. TR146 cells as a model for human buccal epithelium: II. Optimisation and use of a cellular sensitivity MTS\/PMS assay. Int J Pharm 141, 217\u2013225 (1996).","journal-title":"Int J Pharm"},{"key":"BFsrep32498_CR36","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1016\/j.addr.2007.08.019","volume":"59","author":"S Khafagy el","year":"2007","unstructured":"Khafagy el, S., Morishita, M., Onuki, Y. & Takayama, K. Current challenges in non-invasive insulin delivery systems: a comparative review. Adv. Drug. Deliv. Rev. 59, 1521\u20131546, doi: 10.1016\/j.addr.2007.08.019 (2007).","journal-title":"Adv. Drug. Deliv. Rev."},{"key":"BFsrep32498_CR37","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jconrel.2011.01.027","volume":"153","author":"VF Patel","year":"2011","unstructured":"Patel, V. F., Liu, F. & Brown, M. B. Advances in oral transmucosal drug delivery. J. Control. Release 153, 106\u2013116 (2011).","journal-title":"J. Control. Release"},{"key":"BFsrep32498_CR38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/2078-7685.197963","volume":"2","author":"R Kumria","year":"2011","unstructured":"Kumria, R. & Goomber, G. Emerging trends in insulin delivery: Buccal route. J. Diabetol. 2, 1\u20139 (2011).","journal-title":"J. Diabetol"},{"key":"BFsrep32498_CR39","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0168-3659(01)00269-3","volume":"72","author":"S \u015eenel","year":"2001","unstructured":"\u015eenel, S. & H\u0131ncal, A. A. Drug permeation enhancement via buccal route: possibilities and limitations. J. Control. Release 72, 133\u2013144, doi: 10.1016\/S0168-3659(01)00269-3 (2001).","journal-title":"J. Control. Release"},{"key":"BFsrep32498_CR40","first-page":"15","volume":"1","author":"AH Shojaei","year":"1998","unstructured":"Shojaei, A. H. Buccal mucosa as a route for systemic drug delivery: a review. J. Pharm. Pharm. Sci. 1, 15\u201330 (1998).","journal-title":"J. Pharm. Pharm. Sci"},{"key":"BFsrep32498_CR41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2005.01.024","volume":"105","author":"JA Nicolazzo","year":"2005","unstructured":"Nicolazzo, J. A., Reed, B. L. & Finnin, B. C. Buccal penetration enhancers\u2014how do they really work? J. Control. Release 105, 1\u201315 (2005).","journal-title":"J. Control. Release"},{"key":"BFsrep32498_CR42","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0168-3659(99)00032-2","volume":"62","author":"HE Junginger","year":"1999","unstructured":"Junginger, H. E., Hoogstraate, J. A. & Verhoef, J. C. Recent advances in buccal drug delivery and absorption \u2014 in vitro and in vivo studies. J. Control. Release 62, 149\u2013159, doi: 10.1016\/S0168-3659(99)00032-2 (1999).","journal-title":"J. Control. Release"},{"key":"BFsrep32498_CR43","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1007\/s12015-011-9334-7","volume":"8","author":"M Buchert","year":"2012","unstructured":"Buchert, M., Turksen, K. & Hollande, F. Methods to examine tight junction physiology in cancer stem cells: TEER, paracellular permeability, and dilution potential measurements. Stem Cell Rev. 8, 1030\u20131034 (2012).","journal-title":"Stem Cell Rev"},{"key":"BFsrep32498_CR44","doi-asserted-by":"crossref","first-page":"14451","DOI":"10.3390\/molecules200814451","volume":"20","author":"E Moghimipour","year":"2015","unstructured":"Moghimipour, E., Ameri, A. & Handali, S. Absorption-Enhancing Effects of Bile Salts. Molecules 20, 14451\u201314473 (2015).","journal-title":"Molecules"},{"key":"BFsrep32498_CR45","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1007\/s11095-010-0345-x","volume":"28","author":"C Thompson","year":"2011","unstructured":"Thompson, C. et al. Uptake and transport of novel amphiphilic polyelectrolyte-insulin nanocomplexes by Caco-2 cells\u2014towards oral insulin. Pharmaceut. Res. 28, 886\u2013896 (2011).","journal-title":"Pharmaceut. Res."},{"key":"BFsrep32498_CR46","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1043661802002049","volume":"46","author":"H-B Xu","year":"2002","unstructured":"Xu, H.-B. et al. Hypoglycaemic effect of a novel insulin buccal formulation on rabbits. Pharmacol. Res. 46, 459\u2013467, doi: 10.1016\/S1043661802002049 (2002).","journal-title":"Pharmacol. Res"},{"key":"BFsrep32498_CR47","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/jn\/75.1.61","volume":"75","author":"H Sauberlich","year":"1961","unstructured":"Sauberlich, H. Studies on the toxicity and antagonism of amino acids for weanling rats. The J. Nutr. 75, 61\u201372 (1961).","journal-title":"The J. Nutr"},{"key":"BFsrep32498_CR48","unstructured":"Lehr, C.-M. Cell culture models of biological barriers: in vitro test systems for drug absorption and delivery. (CRC Press, 2003)."},{"key":"BFsrep32498_CR49","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nrd4626","volume":"14","author":"L Lin","year":"2015","unstructured":"Lin, L., Yee, S. W., Kim, R. B. & Giacomini, K. M. SLC transporters as therapeutic targets: emerging opportunities. Nat. Rev. Drug Disc. 14(8), 543\u2013560 (2015).","journal-title":"Nat. Rev. Drug Disc."},{"key":"BFsrep32498_CR50","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.addr.2012.09.005","volume":"64","author":"P Artursson","year":"2012","unstructured":"Artursson, P., Palm, K. & Luthman, K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv. Drug Del. Rev. 64, Supplement, 280\u2013289, doi: http:\/\/dx.doi.org\/10.1016\/j.addr.2012.09.005 (2012).","journal-title":"Adv. Drug Del. Rev"},{"key":"BFsrep32498_CR51","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1002\/bmc.616","volume":"20","author":"B Sarmento","year":"2006","unstructured":"Sarmento, B., Ribeiro, A., Veiga, F. & Ferreira, D. Development and validation of a rapid reversed\u2010phase HPLC method for the determination of insulin from nanoparticulate systems. Biomed. Chrom. 20, 898\u2013903 (2006).","journal-title":"Biomed. Chrom"},{"key":"BFsrep32498_CR52","first-page":"620","volume":"58","author":"C Nicolescu","year":"2010","unstructured":"Nicolescu, C., Aram\u0103, C., Nedelcu, A. & Monciu, C.-M. Phase solubility studies of the inclusion complexes of repaglinide with \u03b2-cyclodextrin and \u03b2-cyclodextrin derivatives. Farmacia 58, 620\u2013628 (2010).","journal-title":"Farmacia"},{"key":"BFsrep32498_CR53","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0378-5173(99)00165-9","volume":"185","author":"HM Nielsen","year":"1999","unstructured":"Nielsen, H. M. & Rassing, M. R. TR146 cells grown on filters as a model of human buccal epithelium: III. Permeability enhancement by different pH values, different osmolality values, and bile salts. Int J Pharm 185, 215\u2013225 (1999).","journal-title":"Int J Pharm"},{"key":"BFsrep32498_CR54","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1023\/A:1014220832384","volume":"19","author":"A Portero","year":"2002","unstructured":"Portero, A., Remu\u00f1\u00e1n-L\u00f3pez, C. & Nielsen, H. M. The potential of chitosan in enhancing peptide and protein absorption across the TR146 cell culture model\u2014an in vitro model of the buccal epithelium. Pharmaceutical research 19, 169\u2013174 (2002).","journal-title":"Pharmaceutical research"},{"key":"BFsrep32498_CR55","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.ijpharm.2013.10.026","volume":"458","author":"C Sander","year":"2013","unstructured":"Sander, C., Nielsen, H. M. & Jacobsen, J. Buccal delivery of metformin: TR146 cell culture model evaluating the use of bioadhesive chitosan discs for drug permeability enhancement. Int J Pharm 458, 254\u2013261 (2013).","journal-title":"Int J Pharm"},{"key":"BFsrep32498_CR56","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.carbpol.2006.07.028","volume":"68","author":"A Portero","year":"2007","unstructured":"Portero, A., Teijeiro-Osorio, D., Alonso, M. J. & Remu\u00f1\u00e1n-L\u00f3pez, C. Development of chitosan sponges for buccal administration of insulin. Carbohydrate Polymers 68, 617\u2013625, doi: 10.1016\/j.carbpol.2006.07.028 (2007).","journal-title":"Carbohydrate Polymers"},{"key":"BFsrep32498_CR57","doi-asserted-by":"crossref","unstructured":"Luo Y., Xu H., Huang K., Gao Z., Peng H. & Sheng X. Study on a nanoparticle system for buccal delivery of insulin. Paper presented at 2005 IEEE Engineering in Medicine and Biology Society 27th Annual International Conference, doi: 10.1109\/IEMBS.2005.1615556 (2006 Jan 17).","DOI":"10.1109\/IEMBS.2005.1615556"}],"updated-by":[{"DOI":"10.1038\/srep34883","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T00:00:00Z","timestamp":1476403200000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep32498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep32498","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep32498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T04:32:05Z","timestamp":1718771525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep32498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,1]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,29]]}},"alternative-id":["BFsrep32498"],"URL":"https:\/\/doi.org\/10.1038\/srep32498","relation":{"correction":[{"id-type":"doi","id":"10.1038\/srep34883","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,1]]},"assertion":[{"value":"13 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2016","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has been fixed in the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"32498"}}