{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T21:15:40Z","timestamp":1788556540336,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,7]],"date-time":"2022-05-07T00:00:00Z","timestamp":1651881600000},"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 poor water solubility of apremilast (APR) is the main impediment to the penetration of the drug through the skin barrier. The objective of this study was to evaluate the permeability of APR in different solutions enriched with penetration promoters in ex vivo samples of human skin, and additionally assess its tolerance in vivo. To this end, APR solutions with 5% promoter were developed, and the drug\u2019s ability to penetrate human abdominal skin samples was evaluated; the coefficients of permeability, cumulated amounts permeated, and flow were some of the parameters evaluated; likewise, the in vitro and in vivo tolerance of the solutions was evaluated. The results obtained showed that the solutions containing squalene as a promoter improved the penetration of APR compared to the other promoters evaluated; in the same way, on an in vitro scale in HaCaT cells, the promoters were not toxic, finding a cell viability greater than 80% at the different dilutions evaluated. In the in vivo tests carried out with the solution that presented the best results (APR-Squalene solution), it was observed that it does not cause irritation or erythema on the skin after its colorimetric and histological evaluation of the dorsal region of rats after its application. Squalene becomes an excellent candidate to improve the permeability of the drug in the case of the development of a topical formulation; in addition, it was confirmed that this penetration enhancer is neither toxic nor irritating when in contact with the skin in in vivo tests.<\/jats:p>","DOI":"10.3390\/pharmaceutics14051011","type":"journal-article","created":{"date-parts":[[2022,5,8]],"date-time":"2022-05-08T21:31:20Z","timestamp":1652045480000},"page":"1011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Effect of Penetration Enhancers and Safety on the Transdermal Delivery of Apremilast in Skin"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-635X","authenticated-orcid":false,"given":"Paulo","family":"Sarango-Granda","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"},{"name":"Departamento de Qu\u00edmica, Universidad T\u00e9cnica Particular de Loja, Loja 1101608, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1486-5622","authenticated-orcid":false,"given":"Lupe Carolina","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"},{"name":"Departamento de Qu\u00edmica, Universidad T\u00e9cnica Particular de Loja, Loja 1101608, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-015X","authenticated-orcid":false,"given":"Natalia","family":"D\u00edaz-Garrido","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of the University of Barcelona (IBUB), Sant Joan de D\u00e9u Research Institute, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-8250","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"Rodr\u00edguez-Lagunas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Nutrition and Food Safety Research Institute (INSA-UB), 08921 Santa Coloma de Gramenet, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-269X","authenticated-orcid":false,"given":"Laura","family":"Baldom\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-4821","authenticated-orcid":false,"given":"Ana","family":"Calpena","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"438","DOI":"10.3390\/pharmaceutics7040438","article-title":"Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum","volume":"7","author":"McCrudden","year":"2015","journal-title":"Pharmaceutics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/nbt.1504","article-title":"Transdermal drug delivery","volume":"26","author":"Prausnitz","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"534","DOI":"10.3389\/fimmu.2015.00534","article-title":"Functional specialization of skin dendritic cell subsets in regulating T Cell responses","volume":"6","author":"Clausen","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1111\/pde.14608","article-title":"Fractional CO2 laser-assisted topical rifamycin drug delivery in the treatment of pediatric cutaneous leishmaniasis","volume":"38","author":"Lodi","year":"2021","journal-title":"Pediatric. Dermatol."},{"key":"ref_5","first-page":"159","article-title":"What is the \u2018true\u2019 function of skin?","volume":"11","author":"Kligman","year":"2002","journal-title":"Exp. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1001\/archderm.1991.04520010052006","article-title":"Skin aging: Effect on transepidermal water loss, stratum corneum hydration, skin surface ph, and casual sebum content","volume":"127","author":"Wilhelm","year":"1991","journal-title":"Arch. Dermatol."},{"key":"ref_7","unstructured":"Yousef, H., Alhajj, M., and Sharma, S. (2022). Anatomy, skin (integument), epidermis. StatPearls, StatPearls Publishing."},{"key":"ref_8","unstructured":"Grumezescu, A.M. (2017). Chapter 8\u2014Therapeutic nanostructures for dermal and transdermal drug delivery. Nano- and Microscale Drug Delivery Systems, Elsevier."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1461-5347(00)00295-9","article-title":"Transdermal drug delivery: Overcoming the skin\u2019s barrier function","volume":"3","author":"Naik","year":"2000","journal-title":"Pharm. Sci. Technol. Today"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000211026","article-title":"Role of transepidermal and transfollicular routes in percutaneous absorption of hydrocortisone and testosterone: In vivo study in the hairless rat","volume":"5","author":"Hueber","year":"1992","journal-title":"Skin Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.colsurfb.2008.05.001","article-title":"Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (ocimum sanctum) and turpentine oil","volume":"65","author":"Charoo","year":"2008","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/0169-409X(95)00078-L","article-title":"The role of percutaneous penetration enhancers","volume":"18","author":"Walker","year":"1996","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1461-5347(00)00317-5","article-title":"Non-invasive administration of drugs through the skin: Challenges in delivery system design","volume":"3","author":"Foldvari","year":"2000","journal-title":"Pharm. Sci. Technol. Today"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1007\/s13346-020-00809-1","article-title":"Novel nanocrystal-based formulations of apremilast for improved topical delivery","volume":"11","author":"Parmar","year":"2020","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Guo, J.-W., Cheng, Y.-P., Liu, C.-Y., Thong, H.-Y., Huang, C.-J., Lo, Y., Wu, C.-Y., and Jee, S.-H. (2020). Salvianolic acid B in microemulsion formulation provided sufficient hydration for dry skin and ameliorated the severity of imiquimod-induced psoriasis-like dermatitis in mice. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050457"},{"key":"ref_16","first-page":"105","article-title":"Otezla (apremilast), an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis and plaque psoriasis","volume":"8","author":"Fala","year":"2015","journal-title":"Am. Health Drug Benefits"},{"key":"ref_17","unstructured":"(2022, February 13). FDA Approves OTEZLA\u00ae (apremilast) for the Treatment of Oral Ulcers Associated with Beh\u00e7et\u2019s Disease. Available online: https:\/\/ir.celgene.com\/press-releases-archive\/press-release-details\/2019\/FDA-Approves-OTEZLA-apremilast-for-the-Treatment-of-Oral-Ulcers-Associated-with-Behets-Disease\/default.aspx."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1177\/1203475417748886","article-title":"Management of common side effects of apremilast","volume":"22","author":"Langley","year":"2018","journal-title":"J. Cutan. Med. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111945","DOI":"10.1016\/j.colsurfb.2021.111945","article-title":"Design and dermatokinetic evaluation of apremilast loaded nanostructured lipid carriers embedded gel for topical delivery: A potential approach for improved permeation and prolong skin deposition","volume":"206","author":"Rapalli","year":"2021","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102442","DOI":"10.1016\/j.jddst.2021.102442","article-title":"Solid lipid nanocarriers embedded hydrogel for topical delivery of apremilast: In-vitro, ex-vivo, dermatopharmacokinetic and anti-psoriatic evaluation","volume":"63","author":"Rapalli","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sarango-Granda, P., Silva-Abreu, M., Calpena, A.C., Halbaut, L., F\u00e1brega, M.-J., Rodr\u00edguez-Lagunas, M.J., D\u00edaz-Garrido, N., Badia, J., and Espinoza, L.C. (2020). Apremilast microemulsion as topical therapy for local inflammation: Design, characterization and efficacy evaluation. Pharmaceuticals, 13.","DOI":"10.3390\/ph13120484"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"230","DOI":"10.5530\/ijpi.2021.2.41","article-title":"Formulation, optimization and in vitro evaluation of apremilast nanoemulgel for topical delivery","volume":"11","author":"Mulleria","year":"2021","journal-title":"Int. J. Pharm. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7","DOI":"10.9734\/jpri\/2021\/v33i28B31531","article-title":"Topical delivery of apremilast loaded nanostructured lipid carrier based hydrogel for psoriasis therapy","volume":"33","author":"Sindhoor","year":"2021","journal-title":"J. Pharm. Res. Int."},{"key":"ref_24","unstructured":"(2022, February 14). ICH: Quality Guidelines. Available online: https:\/\/www.ich.org\/page\/quality-guidelines."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zsik\u00f3, S., Cs\u00e1nyi, E., Kov\u00e1cs, A., Budai-Sz\u0171cs, M., G\u00e1csi, A., and Berk\u00f3, S. (2019). Methods to evaluate skin penetration in vitro. Sci. Pharm., 87.","DOI":"10.3390\/scipharm87030019"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.tiv.2014.09.007","article-title":"Suitability of skin integrity tests for dermal absorption studies in vitro","volume":"29","author":"Guth","year":"2015","journal-title":"Toxicol. Vitr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.nano.2019.03.017","article-title":"Nanoemulsion strategy of pioglitazone for the treatment of skin inflammatory diseases","volume":"19","author":"Espinoza","year":"2019","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/cpdd.109","article-title":"The pharmacokinetic effect of coadministration of apremilast and methotrexate in individuals with rheumatoid arthritis and psoriatic arthritis","volume":"3","author":"Liu","year":"2014","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2131\/jts.19.25","article-title":"A simple method for screening assessment of skin and eye irritation","volume":"19","author":"Sekizawa","year":"1994","journal-title":"J. Toxicol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/open.201700040","article-title":"Cationic supramolecular hydrogels for overcoming the skin barrier in drug delivery","volume":"6","author":"Rodrigues","year":"2017","journal-title":"ChemistryOpen"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1039\/C5AY01759A","article-title":"Identification, characterization and HPLC quantification of impurities in apremilast","volume":"8","author":"Xiong","year":"2016","journal-title":"Anal. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"380","DOI":"10.4236\/ajac.2017.86029","article-title":"Development and Validation of stability indicating rapid RP-LC method for determination of process and degradation related impurities of apremilast, an anti-inflammatory drug","volume":"08","author":"Landge","year":"2017","journal-title":"AJAC"},{"key":"ref_33","unstructured":"Panchumarthy, R., Sulthana, S., and Harsha Sri, K. (2020). Development and Validation of a Stability-Indicating Reversed Phase Hplc Method for Determination of Apremilast in Bulk and Pharmaceutical Dosage Form, Scholars Research Library."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1080\/10408347.2020.1718481","article-title":"Analytical methods for determination of apremilast from bulk, dosage form and biological fluids: A critical review","volume":"51","author":"Kulkarni","year":"2020","journal-title":"Crit. Rev. Anal. Chem."},{"key":"ref_35","first-page":"735","article-title":"Apremilast\u2014A review of analytical methods developed for API with its impurities, pharmaceutical formulations and biological matrices","volume":"6","author":"Patel","year":"2021","journal-title":"Int. J. Pharm. Res. Appl."},{"key":"ref_36","unstructured":"(2020, July 15). European Medicines Agency ICH Q2 (R1) Validation of Analytical Procedures: Text and Methodology. Available online: https:\/\/www.ema.europa.eu\/en\/ich-q2-r1-validation-analytical-procedures-text-methodology."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e13370","DOI":"10.1111\/dth.13370","article-title":"Formulation, optimization, and in vitro evaluation of nanostructured lipid carriers for topical delivery of apremilast","volume":"33","author":"Madan","year":"2020","journal-title":"Dermatol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.ijpharm.2017.03.067","article-title":"Solubility and thermodynamics of apremilast in different mono solvents: Determination, correlation and molecular interactions","volume":"523","author":"Shakeel","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.1208\/s12249-018-1196-8","article-title":"Skin penetration and permeation properties of transcutol\u00ae\u2014Neat or diluted mixtures","volume":"19","author":"Osborne","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1080\/10837450802309646","article-title":"Mechanism of in vitro percutaneous absorption enhancement of carvedilol by penetration enhancers","volume":"13","author":"Amin","year":"2008","journal-title":"Pharm. Dev. Technol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/17425247.2020.1713087","article-title":"Permeation enhancers in transdermal drug delivery: Benefits and limitations","volume":"17","year":"2020","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18219","DOI":"10.3390\/molecules201018219","article-title":"Potential of essential oils as penetration enhancers for transdermal administration of ibuprofen to treat dysmenorrhoea","volume":"20","author":"Chen","year":"2015","journal-title":"Molecules"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0378-5173(96)04609-1","article-title":"Mechanisms of action of skin penetration enhancers\/retarders: Azone and analogues","volume":"141","author":"Hadgraft","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1080\/10717544.2018.1523256","article-title":"Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: Permeability and skin deposition study","volume":"25","author":"Haq","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1208\/s12248-008-9012-0","article-title":"Percutaneous permeation enhancement by terpenes: Mechanistic view","volume":"10","author":"Sapra","year":"2008","journal-title":"AAPS J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10507","DOI":"10.3390\/molecules161210507","article-title":"Transdermal drug delivery enhancement by compounds of natural origin","volume":"16","author":"Fox","year":"2011","journal-title":"Molecules"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16883","DOI":"10.1038\/s41598-020-72704-1","article-title":"Vitamin C\u2013squalene bioconjugate promotes epidermal thickening and collagen production in human skin","volume":"10","author":"Gref","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.forsciint.2004.02.041","article-title":"Wipe-test and patch-test for alcohol misuse based on the concentration ratio of fatty acid ethyl esters and squalene CFAEE\/CSQ in skin surface lipids","volume":"143","author":"Pragst","year":"2004","journal-title":"Forensic Sci. Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"540","DOI":"10.3390\/molecules14010540","article-title":"Biological and pharmacological activities of squalene and related compounds: Potential uses in cosmetic dermatology","volume":"14","author":"Huang","year":"2009","journal-title":"Molecules"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/jphp.12334","article-title":"Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: A review","volume":"67","author":"Herman","year":"2015","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ita, K. (2020). Chapter 5\u2014Chemical permeation enhancers. Transdermal Drug Delivery, Academic Press.","DOI":"10.1016\/B978-0-12-822550-9.00005-3"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/S1461-5347(98)00100-X","article-title":"Macromolecules as safe penetration enhancers for hydrophilic drugs\u2014A fiction?","volume":"1","author":"Junginger","year":"1998","journal-title":"Pharm. Sci. Technol. Today"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jid.2019.11.003","article-title":"Research techniques made simple: Cutaneous colorimetry: A reliable technique for objective skin color measurement","volume":"140","author":"Ly","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/srt.12145","article-title":"The seasonal variation in skin hydration, sebum, scaliness, brightness and elasticity in Korean females","volume":"21","author":"Nam","year":"2015","journal-title":"Skin Res. Technol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/5\/1011\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:07:46Z","timestamp":1760137666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/5\/1011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,7]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["pharmaceutics14051011"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14051011","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,7]]}}}