{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T20:22:32Z","timestamp":1788121352792,"version":"build-2803163510"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,5,23]],"date-time":"2021-05-23T00:00:00Z","timestamp":1621728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Oropharyngeal candidiasis (OPC) is a mucosal infection caused by Candida spp., and it is common among the immunocompromised. This condition is mainly treated using oral antifungals. Chlorhexidine (CHD) is a fungicidal and is available as a mouth wash and oral gel. It is used as an adjuvant in the treatment of OPC due to the low residence time of the current formulations. In this study, its activity was tested against C. albicans biofilm and biocompatibility with the HEK293 human cell line. Then, it was formulated as mucoadhesive hydrogel buccal tablets to extend its activity. Different ratios of hydroxypropyl methylcellulose (HPMC), poloxamer 407 (P407), and three different types of polyols were used to prepare the tablets, which were then investigated for their physicochemical properties, ex vivo mucoadhesion, drug release profiles, and the kinetics of drug release. The release was performed using Apparatus I and a controlled flow rate (CFR) method. The results show that CHD is biocompatible and effective against Candida biofilm at a concentration of 20 \u00b5g\/mL. No drug excipient interaction was observed through differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The increase in P407 and polyol ratios showed a decrease in the swelling index and an increase in CHD in vitro release. The release of CHD from the selected formulations was 86\u201392%. The results suggest that chlorhexidine tablets are a possible candidate for the treatment of oropharyngeal candidiasis.<\/jats:p>","DOI":"10.3390\/ph14060493","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:01:20Z","timestamp":1621814480000},"page":"493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Chlorhexidine Mucoadhesive Buccal Tablets: The Impact of Formulation Design on Drug Delivery and Release Kinetics Using Conventional and Novel Dissolution Methods"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6254-8432","authenticated-orcid":false,"given":"Enas","family":"Al-Ani","sequence":"first","affiliation":[{"name":"Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hill","sequence":"additional","affiliation":[{"name":"Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK"},{"name":"School of Biology, Chemistry and Forensic Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3604-9861","authenticated-orcid":false,"given":"Khalid","family":"Doudin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Sheffield, Sheffield S10 2TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S445","DOI":"10.1093\/infdis\/jix131","article-title":"Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment","volume":"216","author":"Arendrup","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"He, J., Thomas, M.A., De Anda, J., Lee, M.W., Van Why, E., Simpson, P., Wong, G.C.L., Grayson, M.H., Volkman, B.F., and Huppler, A.R. (2020). Chemokine CCL28 Is a Potent Therapeutic Agent for Oropharyngeal Candidiasis. Antimicrob. Agents Chemother., 64.","DOI":"10.1128\/AAC.00210-20"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/civ933","article-title":"Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America","volume":"62","author":"Pappas","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1007\/s10096-005-0080-0","article-title":"Erratum: Adverse effects of antifungal therapies in invasive fungal infections: Review and meta-analysis","volume":"25","author":"Girois","year":"2006","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3109\/13693786.2010.505203","article-title":"Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients","volume":"48","author":"Billaud","year":"2010","journal-title":"Med. Mycol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/S0925-4439(02)00087-X","article-title":"The genetic basis of fluconazole resistance development in Candida albicans","volume":"1587","year":"2002","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1093\/jac\/dkh179","article-title":"Second-line therapy with caspofungin for mucosal or invasive candidiasis: Results from the caspofungin compassionate-use study","volume":"53","author":"Kartsonis","year":"2004","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.bcp.2016.11.019","article-title":"Antifungals","volume":"133","author":"Campoy","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1002\/1097-0142(19821215)50:12<2780::AID-CNCR2820501215>3.0.CO;2-P","article-title":"Candida infections in patients with acute leukemia: Ineffectiveness of nystatin prophylaxis and relationship between oropharyngeal and systemic candidiasis","volume":"50","author":"DeGregorio","year":"1982","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.jddst.2018.12.035","article-title":"Formulation and evaluation of fluconazole loaded oral strips for local treatment of oral candidiasis","volume":"49","author":"Karavana","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-5173(03)00371-5","article-title":"Mucoadhesive buccal patches of miconazole nitrate: In vitro\/in vivo performance and effect of ageing","volume":"264","author":"Nafee","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1163\/138577209X12478283327236","article-title":"Polymers in Mucoadhesive Drug-Delivery Systems: A Brief Note","volume":"12","author":"Roy","year":"2009","journal-title":"Des. Monomers Polym."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1208\/s12249-017-0720-6","article-title":"Development and Evaluation of Buccal Films Based on Chitosan for the Potential Treatment of Oral Candidiasis","volume":"18","author":"Tejada","year":"2017","journal-title":"AAPS PharmSciTech"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1080\/03639040500388300","article-title":"Design and Evaluation In Vitro of Controlled Release Mucoadhesive Tablets Containing Chlorhexidine","volume":"32","author":"Ceschel","year":"2006","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1208\/s12249-008-9153-6","article-title":"Preparation, In Vitro Characterization and Preliminary In Vivo Evaluation of Buccal Polymeric Films Containing Chlorhexidine","volume":"9","author":"Juliano","year":"2008","journal-title":"AAPS PharmSciTech"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1517\/17425247.2014.949235","article-title":"Development of an antifungal denture adhesive film for oral candidiasis utilizing hot melt extrusion technology","volume":"12","author":"Park","year":"2015","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/0030-4220(94)90292-5","article-title":"Enhancing the effect of oral hygiene with the use of a foam brush with chlorhexidine","volume":"77","author":"Epstein","year":"1994","journal-title":"Oral Surg. Oral Med. Oral Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"dlaa002","DOI":"10.1093\/jacamr\/dlaa002","article-title":"The potential for developing new antimicrobial resistance from the use of medical devices containing chlorhexidine, minocycline, rifampicin and their combinations: A systematic review","volume":"2","author":"Reitzel","year":"2020","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/j.1600-0757.2009.00338.x","article-title":"Candida biofilms and oral candidosis: Treatment and prevention","volume":"55","author":"Williams","year":"2010","journal-title":"Periodontology 2000"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1464-410X.2011.10837.x","article-title":"The long-term efficacy and safety of a testosterone mucoadhesive buccal tablet in testosterone-deficient men","volume":"110","author":"Dinsmore","year":"2012","journal-title":"BJU Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1067\/mpr.2001.113778","article-title":"A review of saliva: Normal composition, flow, and function","volume":"85","author":"Humphrey","year":"2001","journal-title":"J. Prosthet. Dent."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mulic, A., Tveit, A.B., Songe, D., Sivertsen, H., and Skaare, A.B. (2012). Dental erosive wear and salivary flow rate in physically active young adults. BMC Oral Health, 12.","DOI":"10.1186\/1472-6831-12-8"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1128\/AAC.46.11.3522-3531.2002","article-title":"Action of Chlorhexidine Digluconate against Yeast and Filamentous Forms in an Early-Stage Candida albicans Biofilm","volume":"46","author":"Suci","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1177\/00220345010800031101","article-title":"Antifungal Resistance of Candidal Biofilms Formed on Denture Acrylic in vitro","volume":"80","author":"Chandra","year":"2001","journal-title":"J. Dent. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.mimet.2007.12.005","article-title":"Candida albicans viability after exposure to amphotericin B: Assessment using metabolic assays and colony forming units","volume":"72","author":"Khot","year":"2008","journal-title":"J. Microbiol. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/nprot.2008.75","article-title":"Neutral red uptake assay for the estimation of cell viability\/cytotoxicity","volume":"3","author":"Repetto","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpb.2014.02.005","article-title":"Nanotoxicology applied to solid lipid nanoparticles and nanostructured lipid carriers\u2013A systematic review of in vitro data","volume":"87","author":"Doktorovova","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0939-6411(00)00090-4","article-title":"Hydrogels in pharmaceutical formulations","volume":"50","author":"Peppas","year":"2000","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.eurpolymj.2014.11.024","article-title":"Biomedical applications of hydrogels: A review of patents and commercial products","volume":"65","author":"Khutoryanskiy","year":"2015","journal-title":"Eur. Polym. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.jsps.2019.04.012","article-title":"The effect of the source and the concentration of polymers on the release of chlorhexidine from mucoadhesive buccal tablets","volume":"27","author":"Martin","year":"2019","journal-title":"Saudi Pharm. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jconrel.2006.04.012","article-title":"Buccal bioadhesive drug delivery\u2014A promising option for orally less efficient drugs","volume":"114","author":"Sudhakar","year":"2006","journal-title":"J. Control Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ejpb.2004.03.019","article-title":"In situ-forming hydrogels\u2014review of temperature-sensitive systems","volume":"58","author":"Leroux","year":"2004","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1007\/s11095-006-9104-4","article-title":"A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics","volume":"23","author":"Dumortier","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1007\/s12272-010-1109-1","article-title":"Enhancement of dissolution of nystatin from buccoadhesive tablets containing various surfactants and a solid dispersion formulation","volume":"33","author":"Sakeer","year":"2010","journal-title":"Arch. Pharmacal Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.ijpharm.2014.06.029","article-title":"Thermoresponsive polymers: Insights into decisive hydrogel characteristics, mechanisms of gelation, and promising biomedical applications","volume":"472","author":"Kristl","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1080\/03639040802587799","article-title":"Polyols as filler-binders for disintegrating tablets prepared by direct compaction","volume":"35","author":"Bolhuis","year":"2009","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1016\/j.tripleo.2011.01.039","article-title":"A comparison of salivary substitutes versus a natural sialogogue (citric acid) in patients complaining of dry mouth as an adverse drug reaction: A clinical, randomized controlled study","volume":"112","author":"Femiano","year":"2011","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"fms39","DOI":"10.1111\/j.1365-2621.2004.tb15513.x","article-title":"Effect of Sweet Humectants on Stability and Antimicrobial Action of Sorbates","volume":"69","author":"Gliemmo","year":"2004","journal-title":"J. Food Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1080\/10837450.2018.1425430","article-title":"Influence of processing methods on physico-mechanical properties of Ibuprofen\/HPC-SSL formulation","volume":"23","author":"Chaturvedi","year":"2018","journal-title":"Pharm. Dev. Technol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ejpb.2011.02.005","article-title":"Orally disintegrating mini-tablets (ODMTs)\u2013A novel solid oral dosage form for paediatric use","volume":"78","author":"Stoltenberg","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ijpharm.2004.11.011","article-title":"Analysis of macromolecular changes and drug release from hydrophilic matrix systems","volume":"292","author":"Jamzad","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1007\/BF02980208","article-title":"Preparation of buccal patch composed of carbopol, poloxamer and hydroxypropyl methylcellulose","volume":"26","author":"Chun","year":"2003","journal-title":"Arch. Pharmacal Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1016\/j.addr.2005.07.003","article-title":"The use of mucoadhesive polymers in buccal drug delivery","volume":"57","author":"Chittchang","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ejpb.2007.02.020","article-title":"Release of naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system design","volume":"67","author":"Giannola","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.3109\/03639045.2014.971030","article-title":"Aloin delivery on buccal mucosa:ex vivostudies and design of a new locoregional dosing system","volume":"41","author":"Scaturro","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Di Prima, G., Campisi, G., and De Caro, V. (2020). Amorphous Ropinirole-Loaded Mucoadhesive Buccal Film: A Potential Patient-Friendly Tool to Improve Drug Pharmacokinetic Profile and Effectiveness. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040242"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"De Caro, V., Ajovalasit, A., Sutera, F.M., Murgia, D., Sabatino, M.A., and Dispenza, C. (2017). Development and Characterization of an Amorphous Solid Dispersion of Furosemide in the Form of a Sublingual Bioadhesive Film to Enhance Bioavailability. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9030022"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1002\/jps.20181","article-title":"The Influence of Excipients on Drug Release from Hydroxypropyl Methylcellulose Matrices","volume":"93","author":"Levina","year":"2004","journal-title":"J. Pharm. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1081\/PDT-120003486","article-title":"Investigation of Excipient Type and Level on Drug Release from Controlled Release Tablets Containing HPMC","volume":"7","author":"Williams","year":"2002","journal-title":"Pharm. Dev. Technol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"119983","DOI":"10.1016\/j.ijpharm.2020.119983","article-title":"3D printing of extended-release tablets of theophylline using hydroxypropyl methylcellulose (HPMC) hydrogels","volume":"591","author":"Cheng","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1208\/s12248-010-9185-1","article-title":"DDSolver: An Add-In Program for Modeling and Comparison of Drug Dissolution Profiles","volume":"12","author":"Zhang","year":"2010","journal-title":"AAPS J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0378-5173(89)90306-2","article-title":"A simple equation for the description of solute release. III. Coupling of diffusion and relaxation","volume":"57","author":"Peppas","year":"1989","journal-title":"Int. J. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejpb.2006.12.014","article-title":"Swelling and erosion of pectin matrix tablets and their impact on drug release behavior","volume":"67","author":"Sriamornsak","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0939-6411(99)00082-X","article-title":"Modeling of theophylline release from different geometrical erodible tablets","volume":"49","author":"Karasulu","year":"2000","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1021\/js9600538","article-title":"Modeling of Drug Release from Erodible Tablets","volume":"86","author":"Katzhendler","year":"1997","journal-title":"J. Pharm. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1038\/nprot.2008.141","article-title":"A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing","volume":"3","author":"Pierce","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1007\/BF00547442","article-title":"Tensile fracture of doubly-convex cylindrical discs under diametral loading","volume":"23","author":"Pitt","year":"1988","journal-title":"J. Mater. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0378-5173(95)04416-7","article-title":"In vitro and in vivo nasal mucoadhesion of some water-soluble polymers","volume":"134","author":"Nakamura","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0731-7085(98)00011-9","article-title":"An evaluation of fit factors and dissolution efficiency for the comparison of in vitro dissolution profiles","volume":"17","author":"Anderson","year":"1998","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0928-0987(01)00095-1","article-title":"Modeling and comparison of dissolution profiles","volume":"13","author":"Costa","year":"2001","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1021\/acs.molpharmaceut.7b00477","article-title":"Poloxamer-Decorated Polymer Nanoparticles for Lung Surfactant Compatibility","volume":"14","author":"Bohr","year":"2017","journal-title":"Mol. Pharm."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/6\/493\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:06:18Z","timestamp":1760162778000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/6\/493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,23]]},"references-count":61,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ph14060493"],"URL":"https:\/\/doi.org\/10.3390\/ph14060493","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,23]]}}}