{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:55:49Z","timestamp":1777654549627,"version":"3.51.4"},"reference-count":60,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T00:00:00Z","timestamp":1658793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Labfit-HPRD Lda","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"Labfit-HPRD Lda","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"Laborat\u00f3rios Basi","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"Laborat\u00f3rios Basi","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"EPISKIN","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"EPISKIN","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"CICS-UBI","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"CICS-UBI","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology\/MCTES","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology\/MCTES","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP\/QWP\/708282\/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten\u00ae 10 mg\/g cream was compared with a test product with the same drug strength, along with two \u201cnegative controls\u201d dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.<\/jats:p>","DOI":"10.3390\/pharmaceutics14081554","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T04:59:16Z","timestamp":1658897956000},"page":"1554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Reconstructed Human Epidermis: An Alternative Approach for In Vitro Bioequivalence Testing of Topical Products"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-329X","authenticated-orcid":false,"given":"Ana Sofia","family":"Agonia","sequence":"first","affiliation":[{"name":"Labfit\u2014HPRD Health Products Research and Development, Lda, Edif\u00edcio UBIMEDICAL Estrada Municipal 506, 6200-284 Covilh\u00e3, Portugal"},{"name":"CICS-UBI\u2014Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-358 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-358 Covilh\u00e3, Portugal"}]},{"given":"Ana","family":"Palmeira-de-Oliveira","sequence":"additional","affiliation":[{"name":"Labfit\u2014HPRD Health Products Research and Development, Lda, Edif\u00edcio UBIMEDICAL Estrada Municipal 506, 6200-284 Covilh\u00e3, Portugal"},{"name":"CICS-UBI\u2014Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-358 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-358 Covilh\u00e3, Portugal"}]},{"given":"Catarina","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rios Basi, Mort\u00e1gua, Portugal, Parque Industrial Manuel Louren\u00e7o Ferreira, Lote 15, 3450-232 Mort\u00e1gua, Portugal"}]},{"given":"C\u00e1tia","family":"Augusto","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rios Basi, Mort\u00e1gua, Portugal, Parque Industrial Manuel Louren\u00e7o Ferreira, Lote 15, 3450-232 Mort\u00e1gua, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5431-1432","authenticated-orcid":false,"given":"Christian","family":"Pellevoisin","sequence":"additional","affiliation":[{"name":"EPISKIN, EPISKIN 4, Rue Alexander Fleming, 69366 Lyon, France"}]},{"given":"Christelle","family":"Videau","sequence":"additional","affiliation":[{"name":"EPISKIN, EPISKIN 4, Rue Alexander Fleming, 69366 Lyon, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7430-6297","authenticated-orcid":false,"given":"Ricardo Jorge","family":"Dinis-Oliveira","sequence":"additional","affiliation":[{"name":"TOXRUN\u2014Toxicology Research Unit, University Institute of Health Sciences (IUCS), Advanced Polytechnic and University Cooperative (CESPU), CRL, 4585-116 Gandra, Portugal"},{"name":"Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal"},{"name":"UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4099-002 Porto, Portugal"},{"name":"MTG Research and Development Lab, Rua Professor Joaquim Bastos, 4200-604 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9311-8355","authenticated-orcid":false,"given":"Rita","family":"Palmeira-de-Oliveira","sequence":"additional","affiliation":[{"name":"Labfit\u2014HPRD Health Products Research and Development, Lda, Edif\u00edcio UBIMEDICAL Estrada Municipal 506, 6200-284 Covilh\u00e3, Portugal"},{"name":"CICS-UBI\u2014Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-358 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-358 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,26]]},"reference":[{"key":"ref_1","unstructured":"FDA (2016). Draft Guidance on Acyclovir, U.S. Food and Drug Administration."},{"key":"ref_2","unstructured":"(2014). Guideline on Quality of Transdermal Patches (Standard No. EMA\/CHMP\/QWP\/608924\/2014)."},{"key":"ref_3","unstructured":"(2018). Draft Guideline on Quality and Equivalence of Topical Products (Standard No. CHMP\/QWP\/708282\/2018)."},{"key":"ref_4","unstructured":"OECD (2004). Guidance Document for the Conduct of Skin Absorption Studies, OECD."},{"key":"ref_5","unstructured":"WHO (2006). 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