{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T21:45:53Z","timestamp":1793310353590,"version":"4.5.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100015498","name":"Ministry for Innovation and Technology","doi-asserted-by":"crossref","award":["\u00daNKP-21-4"],"award-info":[{"award-number":["\u00daNKP-21-4"]}],"id":[{"id":"10.13039\/501100015498","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharm Res"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      The aim of our work was to develop a biorelevant dissolution method for a better understanding of the\n                      <jats:italic>in vivo<\/jats:italic>\n                      performance of delayed-release tablet formulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The typical pH profile and residence times in the stomach and small intestine were determined in fasted conditions based on the published results of swallowable monitoring devices. Then, a multi-stage pH shift dissolution method was developed by adding different amounts of phosphate-based buffer solutions to the initial hydrochloric acid solution. Because of the highly variable\n                      <jats:italic>in vivo<\/jats:italic>\n                      residence times in the stomach, two alternatives of the method were applied, modeling rapid and slow gastric emptying as well. This approach provided an opportunity to study the effect of the acidic treatment on post gastric release. Six enteric-coated low-dose acetylsalicylic acid (ASA) formulations including the reference Aspirin Protect were tested as a model compound. Moreover, the thickness of the coating of each formulation was investigated by scanning electron microscope.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comparing the\n                      <jats:italic>in vitro<\/jats:italic>\n                      results to the known properties of the formulations, the new method was found to be more discriminative than the USP dissolution method. Ingredients affecting the\n                      <jats:italic>in vitro<\/jats:italic>\n                      dissolution, and thus probably the\n                      <jats:italic>in vivo<\/jats:italic>\n                      performance, were identified in both the tablet core and the coating of the tested formulations. The limited available\n                      <jats:italic>in vivo<\/jats:italic>\n                      data also indicated an increased predictivity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Overall, the presented method may be an efficient tool to support the development of enteric coated generic formulations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-021-03163-0","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T13:04:24Z","timestamp":1642511064000},"page":"201-211","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Towards a Better Understanding of the Post-Gastric Behavior of Enteric-Coated Formulations"],"prefix":"10.1007","volume":"39","author":[{"given":"Mikl\u00f3s Tam\u00e1s","family":"Katona","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Kakuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9ka","family":"Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Tonka-Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Tak\u00e1cs-Nov\u00e1k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9393-9978","authenticated-orcid":false,"given":"Enik\u0151","family":"Borb\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"3163_CR1","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1023\/A:1016233725612","volume":"12","author":"GL Amidon","year":"1995","unstructured":"Amidon GL. A theorical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:923\u20139.","journal-title":"Pharm Res"},{"key":"3163_CR2","doi-asserted-by":"publisher","first-page":"4209","DOI":"10.1021\/acs.molpharmaceut.6b00877","volume":"14","author":"J Al-Gousous","year":"2017","unstructured":"Al-Gousous J, Tsume Y, Fu M, Salem II, Langguth P. Unpredictable performance of pH-dependent coatings accentuates the need for improved predictive in vitro test systems. Mol Pharm. 2017;14:4209\u201319.","journal-title":"Mol Pharm"},{"key":"3163_CR3","volume-title":"The United States Pharmacopeia and National Formulary USP 29- NF24, Inc.","author":"FDA","year":"2011","unstructured":"FDA. The United States Pharmacopeia and National Formulary USP 29- NF24, Inc. Rockville: The United States Pharmacopeial Convention; 2011."},{"key":"3163_CR4","unstructured":"Council of Europe: European Pharmacopoeia Commission 2.9.3 Dissolution test for solid dosage forms. Eur Pharmacopoeia. 2010;264\u201388."},{"key":"3163_CR5","first-page":"39","volume-title":"Polymers for controlled drug delivery","author":"GA Agylirah","year":"1991","unstructured":"Agylirah GA, Banker GS. Polymers for enteric coating applications. In: Polymers for controlled drug delivery. Boca Raton: CRC Press; 1991. p. 39\u201366."},{"key":"3163_CR6","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1016\/j.ejpb.2013.09.009","volume":"85","author":"A Kambayashi","year":"2013","unstructured":"Kambayashi A, Blume H, Dressman J. Understanding the in vivo performance of enteric coated tablets using an in vitro-in silico-in vivo approach: case example diclofenac. Eur J Pharm Biopharm. 2013;85:1337\u201347.","journal-title":"Eur J Pharm Biopharm"},{"key":"3163_CR7","doi-asserted-by":"crossref","unstructured":"Hasler WL. Duodenal Motility. In Johnson LR, editor. Encyclopedia of Gastroenterology, Academic Press, 2003. p. 636\u201341","DOI":"10.1016\/B0-12-386860-2\/00196-9"},{"key":"3163_CR8","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1517\/17425247.2010.495982","volume":"7","author":"I Locatelli","year":"2010","unstructured":"Locatelli I, Nagelj Kovai N, Mrhar A, Bogataj M. Gastric emptying of non-disintegrating solid drug delivery systems in fasted state: relevance to drug dissolution. Expert Opin Drug Deliv. 2010;7:967\u201376.","journal-title":"Expert Opin Drug Deliv"},{"key":"3163_CR9","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1016\/S0016-5085(84)80178-X","volume":"86","author":"H Minami","year":"1984","unstructured":"Minami H, Mccallum RW. The physiology and pathophysiology of gastric emptying in humans. Gastroenterology. 1984;86:1592\u2013610.","journal-title":"Gastroenterology"},{"key":"3163_CR10","first-page":"1569","volume":"40","author":"N Kaniwaka","year":"1988","unstructured":"Kaniwaka N, Aoyagi N, Ogata H, Ejima A, Motoyama H, Yasumi H. Gastric emptying rates of drug preparations. II. Effects of size and density of enteric-coated drug preparations and food on gastric emptying rates in humans. J Pharmacobiodyn. 1988;40:1569\u201372.","journal-title":"J Pharmacobiodyn"},{"key":"3163_CR11","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1136\/gut.29.8.1035","volume":"29","author":"DF Evans","year":"1988","unstructured":"Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29:1035\u201341.","journal-title":"Gut."},{"key":"3163_CR12","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1111\/j.1365-2036.1989.tb00254.x","volume":"3","author":"J Fallingborg","year":"1989","unstructured":"Fallingborg J, Christensen LA, Ingeman-Nielsen M, Jacobsen BA, Abildgaard K, Rasmussen HH. pH-profile and regional transit times of the normal gut measured by a radiotelemetry device. Aliment Pharmacol Ther. 1989;3:605\u201314.","journal-title":"Aliment Pharmacol Ther"},{"key":"3163_CR13","first-page":"1490","volume":"15","author":"D Becker","year":"2014","unstructured":"Becker D, Zhang J, Heimbach T, Penland RC, Wanke C, Shimizu J, Kulmatycki K. Novel orally swallowable IntelliCap\u00ae device to quantify regional drug absorption in human GI tract using diltiazem as model drug. Ageing Int. 2014;15:1490\u20137.","journal-title":"Ageing Int"},{"key":"3163_CR14","doi-asserted-by":"publisher","first-page":"1828","DOI":"10.1007\/s11095-008-9580-9","volume":"25","author":"VC Ibekwe","year":"2008","unstructured":"Ibekwe VC, Fadda HM, McConnell EL, Khela MK, Evans DF, Basit AW. Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems. Pharm Res. 2008;25:1828\u201335.","journal-title":"Pharm Res"},{"key":"3163_CR15","doi-asserted-by":"publisher","first-page":"2855","DOI":"10.1002\/jps.24274","volume":"104","author":"M Koziolek","year":"2015","unstructured":"Koziolek M, Grimm M, Becker D, Iordanov V, Zou H, Shimizu J, Wanke C, Garbacz G, Weitschies W. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the Intellicap\u00ae system. J Pharm Sci. 2015;104:2855\u201363.","journal-title":"J Pharm Sci"},{"key":"3163_CR16","doi-asserted-by":"publisher","first-page":"e0129076","DOI":"10.1371\/journal.pone.0129076","volume":"10","author":"JM Maurer","year":"2015","unstructured":"Maurer JM, Schellekens RCA, Van Rieke HM, Wanke C, Iordanov V, Stellaard F, et al. Gastrointestinal pH and transit time profiling in healthy volunteers using the IntelliCap system confirms ileo-colonic release of ColoPulse tablets. PLoS ONE. 2015;10:e0129076.","journal-title":"PLoS ONE"},{"key":"3163_CR17","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.ejpb.2016.09.009","volume":"108","author":"F Schneider","year":"2016","unstructured":"Schneider F, Grimm M, Koziolek M, Mode\u00df C, Dokter A, Roustom T, Siegmund W, Weitschies W. Resolving the physiological conditions in bioavailability and bioequivalence studies: comparison of fasted and fed state. Eur J Pharm Biopharm. 2016;108:214\u20139.","journal-title":"Eur J Pharm Biopharm"},{"key":"3163_CR18","first-page":"886","volume":"27","author":"SS Davis","year":"1986","unstructured":"Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Int J Pharm. 1986;27:886\u201392.","journal-title":"Int J Pharm"},{"key":"3163_CR19","unstructured":"Committee for Medicinal Products for Human use, EMA Guideline on the investigation of bioequivalence, 2010"},{"key":"3163_CR20","unstructured":"FDA. Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. 2013."},{"key":"3163_CR21","unstructured":"Drugs.com. American Society of Health-System Pharmacists, Available: https:\/\/www.drugs.com\/monograph\/aspirin.html. 2016. Accessed 09\/10\/2021"},{"key":"3163_CR22","doi-asserted-by":"publisher","first-page":"2218","DOI":"10.1111\/j.1572-0241.2000.02248.x","volume":"95","author":"HT S\u00f8rensen","year":"2000","unstructured":"S\u00f8rensen HT, Mellemkj\u00e6r L, Blot WJ, Nielsen GL, Steffensen FH, McLaughlin JK, et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol. 2000;95:2218\u201324.","journal-title":"Am J Gastroenterol"},{"key":"3163_CR23","doi-asserted-by":"publisher","first-page":"2373","DOI":"10.1056\/NEJMra052717","volume":"3532","author":"C Patrono","year":"2005","unstructured":"Patrono C, Rodrogez LG, Landolfi R, Baigent C. Low-dose aspirin for the prevention of preeclampsia. N Engl J Med. 2005;3532:2373\u201383.","journal-title":"N Engl J Med"},{"key":"3163_CR24","unstructured":"MPA. Public Assessment Report Scientific discussion. Acetylsalicylic acid Krka (acetylsalicylic acid). SE\/H\/1604\/01-03\/DC. 2016;1\u20138."},{"key":"3163_CR25","unstructured":"MPA. Public Assessment Report Scientific discussion. Peneprin (acetylsalicylic acid). SE\/H\/1021\/002005\/DC. 2011."},{"key":"3163_CR26","unstructured":"MPA. Public Assessment Report Scientific discussion. Acetylsalicylsyra Teva (acetylsalicylic acid). SE\/H\/1593\/01-03\/DC. 2016."},{"key":"3163_CR27","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1208\/s12249-013-9933-5","volume":"14","author":"G Garbacz","year":"2013","unstructured":"Garbacz G, Ko\u0142odziej B, Koziolek M, Weitschies W, Klein S. An automated system for monitoring and regulating the pH of bicarbonate buffers. AAPS PharmSciTech. 2013;14:517\u201322.","journal-title":"AAPS PharmSciTech"},{"key":"3163_CR28","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.ejpb.2011.01.001","volume":"78","author":"F Liu","year":"2011","unstructured":"Liu F, Merchant HA, Kulkarni RP, Alkademi M, Basit AW. Evolution of a physiological pH 6.8 bicarbonate buffer system: application to the dissolution testing of enteric coated products. Eur J Pharm Biopharm. 2011;78:151\u20137.","journal-title":"Eur J Pharm Biopharm"},{"key":"3163_CR29","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.ijpharm.2014.09.003","volume":"475","author":"HA Merchant","year":"2014","unstructured":"Merchant HA, Goyanes A, Parashar N, Basit AW. Predicting the gastrointestinal behaviour of modified-release products: Utility of a novel dynamic dissolution test apparatus involving the use of bicarbonate buffers. Int J Pharm. 2014;475:585\u201391.","journal-title":"Int J Pharm"},{"key":"3163_CR30","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1111\/jphp.12540","volume":"68","author":"H Shibata","year":"2016","unstructured":"Shibata H, Yoshida H, Izutsu KI, Goda Y. Use of bicarbonate buffer systems for dissolution characterization of enteric-coated proton pump inhibitor tablets. J Pharm Pharmacol. 2016;68:467\u201374.","journal-title":"J Pharm Pharmacol"},{"key":"3163_CR31","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.1021\/acs.molpharmaceut.6b00077","volume":"13","author":"J Al-Gousous","year":"2016","unstructured":"Al-Gousous J, Amidon GL, Langguth P. Toward biopredictive dissolution for enteric coated dosage forms. Mol Pharm. 2016;13:1927\u201336.","journal-title":"Mol Pharm"},{"key":"3163_CR32","unstructured":"USP. Chapter 724-drug release - delayed-release (enteric-coated)articles-general drug release standard. 2012."},{"key":"3163_CR33","unstructured":"Committe for Medicinal Products for Human Use. Guideline on the investigation of bioequivalence [Internet]. 1997 [cited 2021 Dec 8]. Available from: http:\/\/www.ema.europa.eu."},{"key":"3163_CR34","unstructured":"EMA. ICH guideline M9 on biopharmaceutics classification system based biowaivers. 2018."},{"key":"3163_CR35","unstructured":"Interim Revision Announcement. Aspirin Delayed-Release Tablets. 2017;1\u20132."},{"key":"3163_CR36","unstructured":"USP. Chapter 711 - Dissolution. 2011."},{"key":"3163_CR37","first-page":"326","volume":"10","author":"European Pharmacopoeia","year":"2010","unstructured":"European Pharmacopoeia. 2.9.3. Dissolution test for solid dosage forms. Eur Pharmacopoeia. 2010;10:326\u201333.","journal-title":"Eur Pharmacopoeia"},{"key":"3163_CR38","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1023\/A:1018970323716","volume":"10","author":"TL Russell","year":"1993","unstructured":"Russell TL, Berardi RR, Barnett JL, Dermentzoglou LC, Jarvenpaa KM, Schmaltz SP, et al. Upper gastrointestinal pH in seventy-nine healthy, elderly, north american men and women. Pharm Res. 1993;10:187\u201396 Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/8456064\/.","journal-title":"Pharm Res"}],"container-title":["Pharmaceutical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-021-03163-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11095-021-03163-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-021-03163-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T17:09:24Z","timestamp":1644599364000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11095-021-03163-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["3163"],"URL":"https:\/\/doi.org\/10.1007\/s11095-021-03163-0","relation":{},"ISSN":["0724-8741","1573-904X"],"issn-type":[{"value":"0724-8741","type":"print"},{"value":"1573-904X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"25 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}