{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:13:51Z","timestamp":1790709231000,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T00:00:00Z","timestamp":1554163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2016-04009"],"award-info":[{"award-number":["RGPIN-2016-04009"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Phyto-phospholipid complexes have been developed as a common way of improving the oral bioavailability of poorly absorbable phyto-pharmaceuticals; however, the complexation with phospholipids can induce positive or negative effects on the bioaccessibility of such plant-derived active ingredients in different parts of the gastrointestinal tract (GIT). The purpose of this study was to investigate the effects of phospholipid complexation on the bioaccessibility of a rosmarinic acid-phospholipid complex (RA-PLC) using the TNO dynamic intestinal model-1 (TIM-1). Preparation of RA-PLC was confirmed using X-ray diffraction, Fourier-transform infrared spectroscopy, partition coefficient measurement, and Caco-2 monolayer permeation test. Bioaccessibility parameters in different GIT compartments were investigated. Complexation by phospholipids reduced the bioaccessibility of RA in jejunum compartment, while maintaining the ileum bioaccessibility. The overall bioaccessibility of RA-PLC was lower than the unformulated drug, suggesting that the improved oral absorption from a previous animal study could be considered as a net result of decreased bioaccessibility overwhelmed by enhanced intestinal permeability. This study provides insights into the effects of phospholipid on the bioaccessibility of hydrophilic compounds, and analyzes them based on the relationship between bioaccessibility, membrane permeability, and bioavailability. Additionally, TIM-1 shows promise in the evaluation of dosage forms containing materials with complicated effects on bioaccessibility.<\/jats:p>","DOI":"10.3390\/pharmaceutics11040156","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T03:39:28Z","timestamp":1554262768000},"page":"156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Investigating the Phospholipid Effect on the Bioaccessibility of Rosmarinic Acid-Phospholipid Complex through a Dynamic Gastrointestinal in Vitro Model"],"prefix":"10.3390","volume":"11","author":[{"given":"Jiahao","family":"Huang","sequence":"first","affiliation":[{"name":"School of Pharmacy, University of Waterloo, Waterloo, ON N2L3G1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter X.","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Waterloo, Waterloo, ON N2L3G1, Canada"},{"name":"Department of Food Science, University of Guelph, Guelph, ON N1G2W1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Food Science, University of Guelph, Guelph, ON N1G2W1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6490-264X","authenticated-orcid":false,"given":"Shawn D.","family":"Wettig","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Waterloo, Waterloo, ON N2L3G1, Canada"},{"name":"Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON N2L3G1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,2]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Complexes between phospholipids and vegetal derivates of biological interest","volume":"60","author":"Bombardelli","year":"1989","journal-title":"Fitoterapia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jconrel.2013.02.025","article-title":"Recent advances and future prospects of phyto-phospholipid complexation technique for improving pharmacokinetic profile of plant actives","volume":"168","author":"Khan","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_3","first-page":"940","article-title":"Development and characterization of aspirin-phospholipid complex for improved drug delivery","volume":"3","author":"Semalty","year":"2010","journal-title":"Int. J. Pharm. Sci. Nanotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.3390\/pharmaceutics2040339","article-title":"Enhanced Dissolution and Oral Bioavailability of Piroxicam Formulations: Modulating Effect of Phospholipids","volume":"2","author":"Mirza","year":"2010","journal-title":"Pharmaceutics"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Jo, K., Cho, J.M., Lee, H., Kim, E.K., Kim, H.C., Kim, H., and Lee, J. (2018). Enhancement of Aqueous Solubility and Dissolution of Celecoxib through Phosphatidylcholine-Based Dispersion Systems Solidified with Adsorbent Carriers. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11010001"},{"key":"ref_6","first-page":"352","article-title":"A comparison of gastrointestinal permeability induced by diclofenac-phospholipid complex with diclofenac acid and its sodium salt","volume":"6","author":"Khazaeinia","year":"2003","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1021\/mp900274u","article-title":"Mechanisms of Phospholipid Complex Loaded Nanoparticles Enhancing the Oral Bioavailability","volume":"7","author":"Peng","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.fitote.2009.11.001","article-title":"Supramolecular phospholipids-polyphenolics interactions: The PHYTOSOME (R) strategy to improve the bioavailability of phytochemicals","volume":"81","author":"Semalty","year":"2010","journal-title":"Fitoterapia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ijpharm.2006.09.025","article-title":"Curcumin-phospholipid complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats","volume":"330","author":"Maiti","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jff.2015.09.013","article-title":"Enhanced oral bioavailability and prophylactic effects on oxidative stress and hepatic damage of an oil solution containing a rosmarinic acid-phospholipid complex","volume":"19","author":"Yang","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nm0295-154","article-title":"Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: Insight into the mechanism and reversal of NSAID-induced gastrointestinal injury","volume":"1","author":"Lichtenberger","year":"1995","journal-title":"Nat. Med."},{"key":"ref_12","first-page":"55","article-title":"Product-evaluation registry of Meriva\u00ae, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis","volume":"52","author":"Belcaro","year":"2010","journal-title":"Panminerva Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1083\/jcb.101.2.441","article-title":"Intracellular transport of phosphatidylcholine to the plasma membrane","volume":"101","author":"Kaplan","year":"1985","journal-title":"J. Cell Biol."},{"key":"ref_14","first-page":"209","article-title":"Phytosome: Drug delivery system for polyphenolic phytoconstituents","volume":"7","author":"Singh","year":"2011","journal-title":"Iran. J. Pharm. Sci."},{"key":"ref_15","first-page":"193","article-title":"A review of the bioavailability and clinical efficacy of milk thistle phytosome: A silybin-phosphatidylcholine complex (SiliphosR)","volume":"10","author":"Kidd","year":"2005","journal-title":"Altern. Med. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cmet.2006.03.007","article-title":"The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis","volume":"3","author":"Li","year":"2006","journal-title":"Cell Metab."},{"key":"ref_17","unstructured":"Wirtz-Peitz, F., Probst, M., and Winkelmann, J. (1982). Rosmarinic acid-phospholipide-complex. Google Patents."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.copbio.2008.03.003","article-title":"Nutrients and phytochemicals: From bioavailability to bioefficacy beyond antioxidants","volume":"19","author":"Holst","year":"2008","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"73892","DOI":"10.1039\/C5RA13503F","article-title":"Improving nutraceutical bioavailability using mixed colloidal delivery systems: Lipid nanoparticles increase tangeretin bioaccessibility and absorption from tangeretin-loaded zein nanoparticles","volume":"5","author":"Chen","year":"2015","journal-title":"RSC Adv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jcs.2008.12.001","article-title":"Bioavailability of ferulic acid is determined by its bioaccessibility","volume":"49","author":"Anson","year":"2009","journal-title":"J. Cereal Sci."},{"key":"ref_21","first-page":"1564","article-title":"Pharmacokinetics and Relative Bioavailability Study of Berberine Hydrochloride Phytosome in Rabbits","volume":"17","author":"Han","year":"2011","journal-title":"China Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ejpb.2015.11.013","article-title":"Dual strategies to improve oral bioavailability of oleanolic acid: Enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes","volume":"99","author":"Jiang","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.ijpharm.2014.01.023","article-title":"Solid dispersion of berberine-phospholipid complex\/TPGS 1000\/SiO2: Preparation, characterization and in vivo studies","volume":"465","author":"Zhang","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_24","unstructured":"Weers, J.G., Tarara, T.E., Dellamary, L.A., Riess, J.G., and Schutt, E.G. (2008). Phospholipid-Based Powders for Drug Delivery. (7442388B2), U.S. Patent."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1002\/ejlt.201400219","article-title":"The use of natural and synthetic phospholipids as pharmaceutical excipients","volume":"116","author":"Wendel","year":"2014","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejps.2017.07.008","article-title":"Review\u2014An update on the use of oral phospholipid excipients","volume":"108","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.foodchem.2006.06.025","article-title":"Stability of polyphenols in chokeberry (Aronia melanocarpa) subjected to in vitro gastric and pancreatic digestion","volume":"102","year":"2007","journal-title":"Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"92089","DOI":"10.1039\/C5RA18784B","article-title":"Stability, antioxidant activity and in vitro bile acid-binding of green, black and dark tea polyphenols during simulated in vitro gastrointestinal digestion","volume":"5","author":"Wu","year":"2015","journal-title":"RSC Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1021\/acs.jafc.5b02640","article-title":"Bioaccessibility of Polyphenols from Plant-Processing Byproducts of Black Carrot (Daucus carota L.)","volume":"64","author":"Kamiloglu","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12453","DOI":"10.1021\/jf203096q","article-title":"Phenolic Composition and Antioxidant Activity of Aqueous Infusions from Capparis spinosa L. and Crithmum maritimum L. before and after Submission to a Two-Step in Vitro Digestion Model","volume":"59","author":"Siracusa","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.indcrop.2014.01.049","article-title":"Antioxidant and anti-cholinesterase activities of Lavandula viridis L\u2019Her extracts after in vitro gastrointestinal digestion","volume":"55","author":"Costa","year":"2014","journal-title":"Ind. Crop. Prod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.jff.2016.08.003","article-title":"Bioaccessibility of rutin, caffeic acid and rosmarinic acid: Influence of the in vitro gastrointestinal digestion models","volume":"26","author":"Gayoso","year":"2016","journal-title":"J. Funct. Foods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"225","DOI":"10.4314\/ijhr.v2i3.47905","article-title":"Phytosomes: The new technology for enhancement of bioavailability of botanicals and nutraceuticals","volume":"2","author":"Bhattacharya","year":"2009","journal-title":"Int. J. Health Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1023\/B:PHAM.0000022404.70478.4b","article-title":"A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions","volume":"21","author":"Blanquet","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5763","DOI":"10.1021\/jf203526h","article-title":"Complementary Approaches to Gauge the Bioavailability and Distribution of Ingested Berry Polyphenolics","volume":"60","author":"Lila","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1093\/jn\/133.7.2377","article-title":"Folic acid and 5-methyltetrahydrofolate in fortified milk are bioaccessible as determined in a dynamic in vitro gastrointestinal model","volume":"133","author":"Verwei","year":"2003","journal-title":"J. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.foodhyd.2017.04.015","article-title":"In vitro measurements of luminal viscosity and glucose\/maltose bioaccessibility for oat bran, instant oats, and steel cut oats","volume":"70","author":"AlHasawi","year":"2017","journal-title":"Food Hydrocoll."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/s11483-014-9388-6","article-title":"Biophysical Aspects of Lipid Digestion in Human Breast Milk and SimilacTM Infant Formulas","volume":"10","author":"Fondaco","year":"2015","journal-title":"Food Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1002\/jps.24177","article-title":"Application and Validation of an Advanced Gastrointestinal In Vitro Model for the Evaluation of Drug Product Performance in Pharmaceutical Development","volume":"103","author":"Barker","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1016\/j.chroma.2008.11.030","article-title":"Bioconversion of red ginseng saponins in the gastro-intestinal tract in vitro model studied by high-performance liquid chromatography-high resolution Fourier transform ion cyclotron resonance mass spectrometry","volume":"1216","author":"Kong","year":"2009","journal-title":"J. Chromatogr. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ijpharm.2015.11.048","article-title":"Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms","volume":"498","author":"Verwei","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ejpb.2018.12.010","article-title":"In Vitro Models for the Prediction of in Vivo Performance of Oral Dosage Forms: Recent Progress from Partnership through the IMI OrBiTo Collaboration","volume":"136","author":"Butler","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1080\/10934520701434919","article-title":"Comparison of Five in Vitro Digestion Models to in Vivo Experimental Results: Lead Bioaccessibility in the Human Gastrointestinal Tract","volume":"42","author":"Oomen","year":"2007","journal-title":"J. Environ. Sci. Health Part A"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.foodchem.2014.09.144","article-title":"Phenolic profiles of 20 Canadian lentil cultivars and their contribution to antioxidant activity and inhibitory effects on alpha-glucosidase and pancreatic lipase","volume":"172","author":"Zhang","year":"2015","journal-title":"Food Chem."},{"key":"ref_45","first-page":"197","article-title":"Multicompartmental dynamic computer-controlled model simulating the stomach and small intestine","volume":"23","author":"Minekus","year":"1995","journal-title":"ATLA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22665","DOI":"10.1039\/C4RA15802D","article-title":"Characterization of solid lipid nanoparticles produced with carnauba wax for rosmarinic acid oral delivery","volume":"5","author":"Madureira","year":"2015","journal-title":"RSC Adv."},{"key":"ref_47","unstructured":"Cevc, G. (1993). Phospholipids Handbook, CRC Press."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0304-4157(87)90017-7","article-title":"Lipid intermolecular hydrogen bonding: influence on structural organization and membrane function","volume":"906","author":"Boggs","year":"1987","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","first-page":"217","article-title":"The effect of the proton and of monovalent cations on membrane fluidity","volume":"2","author":"Eibl","year":"1983","journal-title":"Membr. Fluidity Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Marsh, D. (2013). Handbook of Lipid Bilayers, CRC Press.","DOI":"10.1201\/b11712"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0031-9422(02)00513-7","article-title":"Molecules of interest\u2014Rosmarinic acid","volume":"62","author":"Petersen","year":"2003","journal-title":"Phytochemistry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1021\/jf950374p","article-title":"Antioxidant activity of a rosemary extract and its constituents, carnosic acid, carnosol, and rosmarinic acid, in bulk oil and oil-in-water emulsion","volume":"44","author":"Frankel","year":"1996","journal-title":"J. Agric. Food Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.foodchem.2008.01.058","article-title":"Antioxidant activities of rosemary (Rosmarinus Officinalis L.) extract, blackseed (Nigella sativa L.) essential oil, carnosic acid, rosmarinic acid and sesamol","volume":"110","author":"Erkan","year":"2008","journal-title":"Food Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.foodchem.2015.03.100","article-title":"Characterization of free, conjugated and bound phenolics and lipophilic antioxidants in regular- and non-darkening cranberry beans (Phaseolus vulgaris L.)","volume":"185","author":"Chen","year":"2015","journal-title":"Food Chem."},{"key":"ref_55","first-page":"240","article-title":"New insights on oxidative stress in cancer","volume":"12","author":"Visconti","year":"2009","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/0006-291X(91)91647-U","article-title":"Correlation between Oral Drug Absorption in Humans and Apparent Drug Permeability Coefficients in Human Intestinal Epithelial (Caco-2) Cells","volume":"175","author":"Artursson","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/4\/156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:42:23Z","timestamp":1760186543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/4\/156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,2]]},"references-count":56,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["pharmaceutics11040156"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11040156","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,2]]}}}