{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T01:03:48Z","timestamp":1785805428573,"version":"3.56.0"},"reference-count":58,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T00:00:00Z","timestamp":1656288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 \u00b5M), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low\/high BSC permeability class benchmark.<\/jats:p>","DOI":"10.3390\/pharmaceutics14071360","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:07:02Z","timestamp":1656374822000},"page":"1360","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3998-1833","authenticated-orcid":false,"given":"Milica","family":"Markovic","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moran","family":"Zur","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4904-7427","authenticated-orcid":false,"given":"Sapir","family":"Garsiani","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Porat","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8291-791X","authenticated-orcid":false,"given":"Sandra","family":"Cviji\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon L.","family":"Amidon","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-3514","authenticated-orcid":false,"given":"Arik","family":"Dahan","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1023\/A:1016212804288","article-title":"A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability","volume":"12","author":"Amidon","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_2","unstructured":"U.S. Department of Health and Human Services, Food and Drug Administration, Silver Spring, MD, Center for Drug Evaluation and Research (CDER) (2020, November 16). Waiver of In-Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Guidance for Industry, Available online: http:\/\/resource.nlm.nih.gov\/101720038."},{"key":"ref_3","unstructured":"European Medicines Agency ICH M9 Guideline on Biopharmaceutics Classification System-Based Biowaivers, European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-m9-biopharmaceutics-classification-system-based-biowaivers-step-5_en.pdf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1208\/s12248-008-9036-5","article-title":"Application of the biopharmaceutical classification system in clinical drug development--An industrial view","volume":"10","author":"Cook","year":"2008","journal-title":"AAPS J."},{"key":"ref_5","first-page":"273","article-title":"The use of biopharmaceutic classification of drugs in drug discovery and development: Current status and future extension","volume":"57","author":"Abrahamsson","year":"2005","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/clpt.2011.109","article-title":"Bioequivalence of oral products and the biopharmaceutics classification system: Science, regulation, and public policy","volume":"90","author":"Amidon","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1021\/mp300140h","article-title":"The Fraction Dose Absorbed, in Humans, and High Jejunal Human Permeability Relationship","volume":"9","author":"Dahan","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1021\/mp060042f","article-title":"The suitability of an in situ perfusion model for permeability determinations: Utility for BCS class I biowaiver requests","volume":"3","author":"Kim","year":"2006","journal-title":"Mol. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/BF01061407","article-title":"Pharmacokinetic studies on the selective beta1-receptor antagonist metoprolol in man","volume":"2","author":"Borg","year":"1974","journal-title":"J. Pharm. Biopharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/j.1552-4604.1989.tb03307.x","article-title":"The pharmacokinetics of 2.5- to 10-mg oral doses of minoxidil in healthy volunteers","volume":"29","author":"Fleishaker","year":"1989","journal-title":"J. Clin. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/cpt1972133436","article-title":"Pharmacokinetic studies of minoxidil","volume":"13","author":"Gottlieb","year":"1972","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/jps.2600640822","article-title":"Metabolism of minoxidil, a new hypotensive agent II: Biotransformation following oral administration to rats, dogs, and monkeys","volume":"64","author":"Thomas","year":"1975","journal-title":"J. Pharm. Sci."},{"key":"ref_13","first-page":"808","article-title":"Evaluation of minoxidil","volume":"37","author":"Miller","year":"1980","journal-title":"Am. J. Hosp. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1056\/NEJM198010163031607","article-title":"Minoxidil and the treatment of severe hypertension","volume":"303","author":"Pettinger","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1056\/NEJM197307262890401","article-title":"Minoxidil\u2014An alternative to nephrectomy for refractory hypertension","volume":"289","author":"Pettinger","year":"1973","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.2147\/DDDT.S214907","article-title":"Minoxidil and its use in hair disorders: A review, drug design","volume":"13","author":"Suchonwanit","year":"2019","journal-title":"Dev. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.jaad.2019.04.054","article-title":"Effectiveness and safety of low-dose oral minoxidil in male androgenetic alopecia","volume":"81","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hu, M. (2011). Anatomical and physiological factors affecting oral drug bioavailability in rats, dogs, and humans. Oral Bioavailability: Basic Principles, Advanced Concepts, and Applications, Wiley.","DOI":"10.1002\/9781118067598"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1021\/mp500553b","article-title":"Intestinal permeability study of minoxidil: Assessment of minoxidil as a high permeability reference drug for biopharmaceutics classification","volume":"12","author":"Ozawa","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev-physiol-012110-142150","article-title":"Tight junction pore and leak pathways: A dynamic duo","volume":"73","author":"Shen","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3945\/jn.108.100867","article-title":"Quercetin enhances intestinal barrier function through the assembly of zonula [corrected] occludens-2, occludin, and claudin-1 and the expression of claudin-4 in Caco-2 cells","volume":"139","author":"Suzuki","year":"2009","journal-title":"J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Valenzano, M.C., DiGuilio, K., Mercado, J., Teter, M., To, J., Ferraro, B., Mixson, B., Manley, I., Baker, V., and Moore, B.A. (2015). Remodeling of tight junctions and enhancement of barrier integrity of the CACO-2 intestinal epithelial cell layer by micronutrients. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0133926"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1021\/mp3001414","article-title":"Sodium caprate transiently opens claudin-5-containing barriers at tight junctions of epithelial and endothelial cells","volume":"9","author":"Tscheik","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_24","first-page":"105440","article-title":"Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability","volume":"152","author":"Markovic","year":"2020","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Markovic, M., Zur, M., Fine-Shamir, N., Haimov, E., Gonz\u00e1lez-\u00c1lvarez, I., and Dahan, A. (2020). Segmental-dependent solubility and permeability as key factors guiding controlled release drug product development. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12030295"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ijpharm.2015.05.002","article-title":"The biopharmaceutics of successful controlled release drug product: Segmental-dependent permeability of glipizide vs. metoprolol throughout the intestinal tract","volume":"489","author":"Zur","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1021\/mp500152y","article-title":"The low\/high BCS permeability class boundary: Physicochemical comparison of metoprolol and labetalol","volume":"11","author":"Zur","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/BF01060026","article-title":"Quantitaton of rate of gastrointestinal and buccal absorption of acidic and basic drugs based on extraction theory","volume":"1","author":"Wagner","year":"1973","journal-title":"J. Pharmacokinet. Biopharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/BF01064809","article-title":"Shift of pH-absorption curves","volume":"5","author":"Winne","year":"1977","journal-title":"J. Pharmacokinet. Biopharm."},{"key":"ref_30","unstructured":"Hansch, C., Leo, A., and Hoekman, D.H. (1995). Exploring QSAR: Hydrophobic, electronic, and steric constants. ACS Professional Reference Book, American Chemical Society."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1007\/s00216-009-2862-1","article-title":"Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections","volume":"394","author":"Henchoz","year":"2009","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jconrel.2006.08.020","article-title":"Ion pair-mediated transport of metoprolol across a three lipid-component PAMPA system","volume":"116","author":"Teksin","year":"2006","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/S0731-7085(96)01977-2","article-title":"Protolytic constants of nizatidine, ranitidine and N,N\u2032-dimethyl-2-nitro-1,1-ethenediamine; spectrophotometric and theoretical investigation","volume":"15","author":"Dumanovic","year":"1997","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_34","unstructured":"Florey, K. (1990). Nizatidine. Analytical Profiles of Drug Substance, Academic Press."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Avdeef, A. (2012). Permeability: Caco-2\/MDCK. Absorption and Drug Development, John Wiley & Sons, Inc.","DOI":"10.1002\/9781118286067"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1023\/A:1011076217118","article-title":"A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells","volume":"18","author":"Gao","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_37","first-page":"320","article-title":"Segmental-dependent membrane permeability along the intestine following oral drug administration: Evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat","volume":"36","author":"Dahan","year":"2009","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_38","first-page":"1","article-title":"Closed-loop doluisio (colon, small intestine) and single-pass intestinal perfusion (colon, jejunum) in rat\u2014biophysical model and predictions based on Caco-2","volume":"35","author":"Zur","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ijpharm.2016.09.061","article-title":"Segmental-dependent permeability throughout the small intestine following oral drug administration: Single-pass vs. Doluisio approach to in-situ rat perfusion","volume":"515","author":"Zur","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ijpharm.2017.05.018","article-title":"Investigating drug absorption from the colon: Single-pass vs. Doluisio approaches to in-situ rat large-intestinal perfusion","volume":"527","author":"Zur","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2015.01.014","article-title":"In-situ intestinal rat perfusions for human fabs prediction and BCS permeability class determination: Investigation of the single-pass vs. the doluisio experimental approaches","volume":"480","author":"Zur","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1124\/dmd.109.028282","article-title":"Multiple efflux pumps are involved in the transepithelial transport of colchicine: Combined effect of p-glycoprotein and multidrug resistance-associated protein 2 leads to decreased intestinal absorption throughout the entire small intestine","volume":"37","author":"Dahan","year":"2009","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1021\/mp100175a","article-title":"High-permeability criterion for BCS classification: Segmental\/pH dependent permeability considerations","volume":"7","author":"Dahan","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.xphs.2018.07.017","article-title":"Segmental-dependent intestinal drug permeability: Development and model validation of in silico predictions guided by in vivo permeability values","volume":"108","author":"Wolk","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_45","unstructured":"Mannhold, R., Kubinyi, H., Folkers, G., van de Waterbeemd, H., Lennern\u00e4s, H., and Artursson, P. (2003). Simulation of absorption, metabolism, and bioavailability. Drug Bioavailability, Wiley."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lin, L., and Wong, H. (2017). Predicting oral drug absorption: Mini review on physiologically-based pharmacokinetic models. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9040041"},{"key":"ref_47","first-page":"153","article-title":"Formulation and in vitro evaluation of minoxidil topical gel","volume":"11","author":"Parhi","year":"2014","journal-title":"Turk. J. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s12247-019-09404-5","article-title":"In vitro and in vivo assessment of the potential of supersaturation to enhance the absorption of poorly soluble basic drug","volume":"15","author":"Li","year":"2020","journal-title":"J. Pharm. Innov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7","DOI":"10.14205\/2309-4435.2015.03.01.2","article-title":"Confidence assessment of an absorption model using limited solubility and permeability data for 21 drugs within a dynamic physiologically-based pharmacokinetic simulator","volume":"3","author":"Wang","year":"2015","journal-title":"J. Appl. Biopharm. Pharmacokinet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1124\/dmd.118.082966","article-title":"Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 1352 drug compounds","volume":"46","author":"Lombardo","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/(SICI)1099-081X(1998110)19:8<501::AID-BDD127>3.0.CO;2-G","article-title":"Pharmacokinetics of minoxidil in patients with cirrhosis and healthy volunteers","volume":"19","author":"Adams","year":"1998","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_52","unstructured":"(2020, December 15). Loniten\u00aeminoxidil Tablets. United States Pharmacopeia, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/018154s026lbl.pdf."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.1097\/00005344-198000022-00002","article-title":"Pharmacology and pharmacokinetics of minoxidil","volume":"2","author":"Lowenthal","year":"1980","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/nyas.13360","article-title":"Intestinal epithelial claudins: Expression and regulation in homeostasis and inflammation","volume":"1397","author":"Quiros","year":"2017","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s10620-019-05777-2","article-title":"The \u201cLeaky Gut\u201d: Tight junctions but loose associations?","volume":"65","author":"Hollander","year":"2020","journal-title":"Dig. Dis. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1016\/0016-5085(95)90708-4","article-title":"Intestinal permeability: An overview","volume":"108","author":"Bjarnason","year":"1995","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12915-018-0481-z","article-title":"Marked differences in tight junction composition and macromolecular permeability among different intestinal cell types","volume":"16","author":"Pearce","year":"2018","journal-title":"BMC Biol."},{"key":"ref_58","unstructured":"National Center for Biotechnology Information (2020, November 16). PubChem Compound Summary for CID 4201, Minoxidil, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Minoxidil."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/7\/1360\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:11Z","timestamp":1760139551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/7\/1360"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,27]]},"references-count":58,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["pharmaceutics14071360"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14071360","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,27]]}}}