{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:59:02Z","timestamp":1793120342599,"version":"4.5.0"},"reference-count":94,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T00:00:00Z","timestamp":1608508800000},"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>Apremilast (APR) is a selective phosphodiesterase 4 inhibitor administered orally in the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. The low solubility and permeability of this drug hinder its dermal administration. The purpose of this study was to design and characterize an apremilast-loaded microemulsion (APR-ME) as topical therapy for local skin inflammation. Its composition was determined using pseudo-ternary diagrams. Physical, chemical and biopharmaceutical characterization were performed. Stability of this formulation was studied for 90 days. Tolerability of APR-ME was evaluated in healthy volunteers while its anti-inflammatory potential was studied using in vitro and in vivo models. A homogeneous formulation with Newtonian behavior and droplets of nanometric size and spherical shape was obtained. APR-ME released the incorporated drug following a first-order kinetic and facilitated drug retention into the skin, ensuring a local effect. Anti-inflammatory potential was observed for its ability to decrease the production of IL-6 and IL-8 in the in vitro model. This effect was confirmed in the in vivo model histologically by reduction in infiltration of inflammatory cells and immunologically by decrease of inflammatory cytokines IL-8, IL-17A and TNF\u03b1. Consequently, these results suggest that this formulation could be used as an attractive topical treatment for skin inflammation.<\/jats:p>","DOI":"10.3390\/ph13120484","type":"journal-article","created":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T09:41:41Z","timestamp":1608543701000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Apremilast Microemulsion as Topical Therapy for Local Inflammation: Design, Characterization and Efficacy Evaluation"],"prefix":"10.3390","volume":"13","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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9906-049X","authenticated-orcid":false,"given":"Marcelle","family":"Silva-Abreu","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"}]},{"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"}]},{"given":"Lyda","family":"Halbaut","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0205-3750","authenticated-orcid":false,"given":"Mar\u00eda-Jos\u00e9","family":"F\u00e1brega","sequence":"additional","affiliation":[{"name":"Department of Experimental and Health Sciences, Parc de Recerca Biom\u00e8dica de Barcelona, University Pompeu Fabra (UPF), 08005 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-8250","authenticated-orcid":false,"given":"Mar\u00eda","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\/0000-0003-1220-015X","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-8250","authenticated-orcid":false,"given":"Josefa","family":"Badia","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\/0000-0003-1486-5622","authenticated-orcid":false,"given":"Lupe","family":"Espinoza","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"},{"name":"Departamento de Qu\u00edmica y Ciencias Exactas, Universidad T\u00e9cnica Particular de Loja, Loja 1101608, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.cell.2010.03.006","article-title":"Inflammation 2010: New adventures of an old flame","volume":"140","author":"Medzhitov","year":"2010","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jdermsci.2014.08.010","article-title":"Classification of inflammatory skin diseases: A proposal based on the disorders of the three-layered defense systems, barrier, innate immunity and acquired immunity","volume":"76","author":"Dainichi","year":"2014","journal-title":"J. Dermatol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40744-014-0005-4","article-title":"Apremilast: A phosphodiesterase 4 inhibitor for the treatment of psoriatic arthritis","volume":"1","author":"Mease","year":"2014","journal-title":"Rheumatol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Raker, V.K., Becker, C., and Steinbrink, K. (2016). The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00123"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1517\/14656566.2015.1034107","article-title":"Apremilast: A PDE4 inhibitor for the treatment of psoriatic arthritis","volume":"16","author":"Abdulrahim","year":"2015","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_7","first-page":"495","article-title":"Apremilast (otezla): A new oral treatment for adults with psoriasis and psoriatic arthritis","volume":"40","author":"Zerilli","year":"2015","journal-title":"Drug Forecast"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1021\/jm900210d","article-title":"Discovery of (S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo2,3-dihydro-1H-isoindol-4-yl}acetamide (Apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-\u03b1 inhibitor","volume":"52","author":"Man","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/idoj.IDOJ_437_18","article-title":"Apremilast in psoriasis and beyond: Big hopes on a small molecule","volume":"10","author":"Afra","year":"2019","journal-title":"Indian Dermatol. Online J."},{"key":"ref_10","first-page":"191","article-title":"A review of 2014 cancer drug approvals, with a look at 2015 and beyond","volume":"40","author":"Butler","year":"2015","journal-title":"P T"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.bcp.2012.01.001","article-title":"Apremilast mechanism of action and application to psoriasis and psoriatic arthritis","volume":"83","author":"Schafer","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kumar, N., Goldminz, A.M., Kim, N., and Gottlieb, A.B. (2013). Phosphodiesterase 4-targeted treatments for autoimmune diseases. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-96"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.2147\/IJN.S195048","article-title":"Preparation of sustained release apremilast-loaded PLGA nanoparticles: In vitro characterization and in vivo pharmacokinetic study in rats","volume":"14","author":"Anwer","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101844","DOI":"10.1016\/j.jddst.2020.101844","article-title":"In vitro-in silico evaluation of Apremilast solid dispersions prepared via Corotating Twin Screw Extruder","volume":"59","author":"Muvva","year":"2020","journal-title":"J. Drug Deliv. Sci. Tech."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Madan, J.R., Khobaragade, S., Dua, K., and Awasthi, R. (2020). Formulation, optimization, and in vitro evaluation of nanostructured lipid carriers for topical delivery of Apremilast. Dermatol. Ther.","DOI":"10.3762\/bxiv.2020.7.v1"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Parmar, P.K., and Bansal, A.K. (2020). Novel nanocrystal-based formulations of apremilast for improved topical delivery. Drug Deliv. Transl. Res.","DOI":"10.1007\/s13346-020-00809-1"},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.colsurfb.2016.03.026","article-title":"Diclofenac acid nanocrystals as an effective strategy to reduce in vivo skin inflammation by improving dermal drug bioavailability","volume":"143","author":"Pireddu","year":"2016","journal-title":"Colloids Surf. B"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1080\/10717540500455975","article-title":"Dermal and transdermal drug delivery systems: Current and future prospects","volume":"13","author":"Brown","year":"2006","journal-title":"Drug Deliv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/jat.3262","article-title":"Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption: SC reservoir to predict in vitro percutaneous absorption","volume":"36","author":"Hafeez","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3109\/10717544.2014.935532","article-title":"Permeation enhancer strategies in transdermal drug delivery","volume":"23","author":"Marwah","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.addr.2017.08.009","article-title":"Device-assisted transdermal drug delivery","volume":"127","author":"Lee","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_23","unstructured":"European Medicines Agency (2014). Assessment Report: Otezla, EMA."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nastiti, C., Ponto, T., Abd, E., Grice, J., Benson, H., and Roberts, M. (2017). Topical Nano and Microemulsions for Skin Delivery. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9040037"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ijpharm.2018.04.049","article-title":"Development of microemulsions of suitable viscosity for cyclosporine skin delivery","volume":"545","author":"Benigni","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113449","DOI":"10.1016\/j.molliq.2020.113449","article-title":"The synthesis of methotrexate-loaded F127 microemulsions and their in vivo toxicity in a rat model","volume":"313","author":"Rahdar","year":"2020","journal-title":"J. Mol. Liq."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ijpharm.2017.07.036","article-title":"Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro\/in vivo performances","volume":"529","author":"Mitsou","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shewaiter, M.A., Hammady, T.M., El-Gindy, A., Hammadi, S.H., and Gad, S. (2020). Formulation and characterization of leflunomide\/diclofenac sodium microemulsion base-gel for the transdermal treatment of inflammatory joint diseases. J. Drug Deliv. Sci. Tech., 102110.","DOI":"10.1016\/j.jddst.2020.102110"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.ijpharm.2013.03.054","article-title":"Lipid-based formulations for oral administration of poorly water-soluble drugs","volume":"453","author":"Mu","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bhushan, B. (2012). Dermal and Transdermal Delivery. Encyclopedia of Nanotechnology, Springer.","DOI":"10.1007\/978-90-481-9751-4"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.foodres.2007.09.006","article-title":"Characterization and stability evaluation of \u03b2-carotene nanoemulsions prepared by high pressure homogenization under various emulsifying conditions","volume":"41","author":"Yuan","year":"2008","journal-title":"Food Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/1541-4337.12405","article-title":"Nanoemulsions: Synthesis, Characterization, and Application in Bio-Based Active Food Packaging","volume":"18","author":"Espitia","year":"2019","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1016\/j.jid.2017.02.196","article-title":"181 Global skin disease morbidity and mortality: An update from the Global Burden of Disease Study 2013","volume":"137","author":"Dellavalle","year":"2017","journal-title":"J. Invest Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s13671-017-0192-7","article-title":"Global Burden of Skin Disease: Inequities and Innovations","volume":"6","author":"Seth","year":"2017","journal-title":"Curr. Derm. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhang, X., Wang, A., Shi, T., Zhang, J., Xu, H., Wang, D., and Feng, L. (2019). The psychosocial adaptation of patients with skin disease: A scoping review. BMC Public Health, 19.","DOI":"10.1186\/s12889-019-7775-0"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zamora, N.V., Valerio-Morales, I.-A., Lopez-Olivo, M.A., Pan, X., and Suarez-Almazor, M.E. (2016). Phosphodiesterase 4 inhibitors for psoriatic arthritis. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD012401"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1136\/annrheumdis-2019-215437","article-title":"Real-world effectiveness of apremilast in multirefractory mucosal involvement of Beh\u00e7et\u2019s disease","volume":"78","author":"Lopalco","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_38","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_39","unstructured":"Kulkarni, P., and Deshpande, A. (2020). Analytical methods for determination of apremilast from bulk, dosage form and biological fluids: A critical review. Crit. Rev. Anal. Chem., 1\u201310."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1590\/S1984-82502011000300003","article-title":"Self-emulsifying therapeutic system: A potential approach for delivery of lipophilic drugs","volume":"47","author":"Wadhwa","year":"2011","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_41","first-page":"46","article-title":"Microemulsions as nano-carriers for nutraceuticals: Current trends and the future outlook","volume":"12","author":"Abbasi","year":"2017","journal-title":"EC Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1439-0507.2012.02202.x","article-title":"Evaluation of novel nystatin nanoemulsion for skin candidosis infections: Nystatin nanoemulsion for skin candidosis","volume":"56","year":"2013","journal-title":"Mycoses"},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ijpharm.2015.12.010","article-title":"Evaluation of the versatile character of a nanoemulsion formulation","volume":"498","author":"Since","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.fjps.2017.07.003","article-title":"Enhanced transdermal permeability of Terbinafine through novel nanoemulgel formulation; Development, in vitro and in vivo characterization","volume":"4","author":"Elmataeeshy","year":"2018","journal-title":"Future J. Pharm. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11743-014-1618-x","article-title":"Structure of microemulsion formulated with monoacylglycerols in the presence of polyols and ethanol","volume":"18","year":"2015","journal-title":"J. Surfactants Deterg."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00403-014-1484-4","article-title":"Semisolid formulations containing cetirizine: Human skin permeation and topical antihistaminic evaluation in a rabbit model","volume":"306","author":"Ciurlizza","year":"2014","journal-title":"Arch. Dermatol. Res."},{"key":"ref_48","first-page":"1125","article-title":"Preparation, characterization and stability study of dutasteride loaded nanoemulsion for treatment of benign prostatic hypertrophy","volume":"13","author":"Ali","year":"2014","journal-title":"Iran J. Pharm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zhang, Z., and McClements, D.J. (2018). Overview of Nanoemulsion Properties: Stability, Rheology, and Appearance. Nanoemulsions, Elsevier.","DOI":"10.1016\/B978-0-12-811838-2.00002-3"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.foodhyd.2016.11.033","article-title":"Rheological and release properties of double nano-emulsions containing crocin prepared with Angum gum, Arabic gum and whey protein","volume":"66","author":"Mehrnia","year":"2017","journal-title":"Food Hydrocoll."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Salamanca, C., Barrera-Ocampo, A., Lasso, J., Camacho, N., and Yarce, C. (2018). Franz diffusion cell approach for pre-formulation characterisation of ketoprofen semi-solid dosage forms. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10030148"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1208\/s12248-012-9337-6","article-title":"The solubility\u2013permeability interplay and its implications in formulation design and development for poorly soluble drugs","volume":"14","author":"Dahan","year":"2012","journal-title":"AAPS J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1007\/s11095-017-2181-8","article-title":"Developing transdermal applications of ketorolac tromethamine entrapped in stimuli sensitive block copolymer hydrogels","volume":"34","author":"Mallandrich","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1159\/000235827","article-title":"Experimental models in predicting topical antifungal efficacy: Practical aspects and challenges","volume":"22","author":"Lai","year":"2009","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_55","first-page":"163","article-title":"Skin models for the testing of transdermal drugs","volume":"8","author":"Abd","year":"2016","journal-title":"Clin. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Schafer, P.H., Chen, P., Fang, L., Wang, A., and Chopra, R. (2015). The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: Substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J. Immunol. Res., 906349.","DOI":"10.1155\/2015\/906349"},{"key":"ref_57","first-page":"D112","article-title":"Phospholipid, arachidonate and eicosanoid signaling in schizophrenia","volume":"23","author":"Messamore","year":"2016","journal-title":"Oilseeds Fats Crops Lipids"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1042\/BST20160469","article-title":"Fatty acids and related lipid mediators in the regulation of cutaneous inflammation","volume":"46","author":"Kendall","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jfda.2014.05.004","article-title":"Inhibitory activity of Sargassum hemiphyllum sulfated polysaccharide in arachidonic acid-induced animal models of inflammation","volume":"23","author":"Hwang","year":"2015","journal-title":"J. Food Drug Anal."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.bbalip.2014.07.008","article-title":"Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors","volume":"1851","author":"Kawahara","year":"2015","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/ptr.4695","article-title":"Topical antiinflammatory activity of essential oil of Lippia sidoides Cham: Possible Mechanism of Action","volume":"27","author":"Veras","year":"2013","journal-title":"Phytother. Res."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Toda, K., Tsukayama, I., Nagasaki, Y., Konoike, Y., Tamenobu, A., Ganeko, N., Ito, H., Kawakami, Y., Takahashi, Y., and Miki, Y. (2020). Red-kerneled rice proanthocyanidin inhibits arachidonate 5-lipoxygenase and decreases psoriasis-like skin inflammation. Arch. Biochem., 108307.","DOI":"10.1016\/j.abb.2020.108307"},{"key":"ref_63","first-page":"835","article-title":"Mechanisms underlying the clinical effects of apremilast for psoriasis","volume":"17","author":"Pincelli","year":"2018","journal-title":"J. Drugs Dermatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.fct.2018.04.041","article-title":"HPLC profile and antiedematogenic activity of Ximenia americana L. (Olacaceae) in mice models of skin inflammation","volume":"119","author":"Fernandes","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jdermsci.2017.03.004","article-title":"Topical application of glycolic acid suppresses the UVB induced IL-6, IL-8, MCP-1 and COX-2 inflammation by modulating NF-\u03baB signaling pathway in keratinocytes and mice skin","volume":"86","author":"Tang","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/j.0022-202X.2005.23831.x","article-title":"Topical application of a novel immunomodulatory peptide, RDP58, reduces skin inflammation in the phorbol ester-induced dermatitis model","volume":"125","author":"Valdez","year":"2005","journal-title":"J. Invest Dermatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.jid.2018.09.021","article-title":"Antagonization of IL-17A attenuates skin inflammation and vascular dysfunction in mouse models of psoriasis","volume":"139","author":"Brand","year":"2019","journal-title":"J. Invest Dermatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1038\/s41598-020-60966-8","article-title":"Effects of chloromethylisothiazolinone\/methylisothiazolinone (CMIT\/MIT) on Th2\/Th17-related immune modulation in an atopic dermatitis mouse model","volume":"10","author":"Go","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1080\/1744666X.2020.1685382","article-title":"TNF-alpha inhibitors for the six treatment targets of psoriatic arthritis","volume":"15","author":"Lubrano","year":"2019","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"53","DOI":"10.2174\/187152809787582543","article-title":"TNF-\u03b1 in tuberculosis: A cytokine with a split personality","volume":"8","author":"Mootoo","year":"2009","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.canlet.2012.10.014","article-title":"Tumor necrosis factor","volume":"328","author":"Chu","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.intimp.2015.07.036","article-title":"Anti-TNF-\u03b1 monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis","volume":"28","author":"Liu","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.phrs.2017.11.012","article-title":"Topical administration of reversible SAHH inhibitor ameliorates imiquimod-induced psoriasis-like skin lesions in mice via suppression of TNF-\u03b1\/IFN-\u03b3-induced inflammatory response in keratinocytes and T cell-derived IL-17","volume":"129","author":"Lin","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1080\/17425255.2016.1206886","article-title":"Pharmacodynamic assessment of apremilast for the treatment of moderate-to-severe plaque psoriasis","volume":"12","author":"Bianchi","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000087019","article-title":"Localization of IL-8 and Complement Components in Lesional Skin of Psoriasis vulgaris and Pustulosis palmaris et plantaris","volume":"211","author":"Ozawa","year":"2005","journal-title":"Dermatology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/1523-1747.ep12371677","article-title":"IL-8 gene expression and production in human keratinocytes and their modulation by UVB","volume":"101","author":"Kondo","year":"1993","journal-title":"J. Invest Dermatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/ijd.14695","article-title":"IL-17 and its role in inflammatory, autoimmune, and oncological skin diseases: State of art","volume":"59","author":"Bernardini","year":"2020","journal-title":"Int. J. Dermatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.molmed.2016.01.001","article-title":"IL-17 in chronic inflammation: From discovery to targeting","volume":"22","author":"Beringer","year":"2016","journal-title":"Trends Mol. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41598-020-57542-5","article-title":"Large-scale analyses of disease biomarkers and apremilast pharmacodynamic effects","volume":"10","author":"Medvedeva","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"11596","DOI":"10.1038\/srep11596","article-title":"Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections","volume":"5","author":"Thangamani","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3390\/jfb5020043","article-title":"HaCaT keratinocytes response on antimicrobial atelocollagen substrates: Extent of cytotoxicity, cell viability and proliferation","volume":"5","year":"2014","journal-title":"J. Funct. Biomater."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Souto, E.B., Zielinska, A., Souto, S.B., Durazzo, A., Lucarini, M., Santini, A., Silva, A.M., Atanasov, A.G., Marques, C., and Andrade, L.N. (2020). (+)-Limonene 1,2-epoxide-loaded slns: Evaluation of drug release, antioxidant activity, and cytotoxicity in an HaCaT cell line. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041449"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"119312","DOI":"10.1016\/j.ijpharm.2020.119312","article-title":"Evaluating two nanocarrier systems for the transdermal delivery of sodium alendronate","volume":"582","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"119256","DOI":"10.1016\/j.ijpharm.2020.119256","article-title":"Development of flavanone and its derivatives as topical agents against psoriasis: The prediction of therapeutic efficiency through skin permeation evaluation and cell-based assay","volume":"581","author":"Alalaiwe","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.annder.2018.03.004","article-title":"Hydratation cutan\u00e9e et produits hydratants","volume":"145","author":"Duplan","year":"2018","journal-title":"Ann. Dermatol. Venereol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1111\/j.0906-6705.2005.00341.x","article-title":"Stratum corneum hydration and flexibility are useful parameters to indicate clinical severity of congenital ichthyosis","volume":"14","author":"Tomita","year":"2005","journal-title":"Exp. Dermatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jtv.2016.10.003","article-title":"Effects of two different fabrics on skin barrier function under real pressure conditions","volume":"26","author":"Schario","year":"2017","journal-title":"J. Tissue Viability"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.tiv.2018.04.009","article-title":"Transepidermal water loss and skin conductance as barrier integrity tests","volume":"51","author":"Zhang","year":"2018","journal-title":"Toxicol. In Vitro"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1111\/srt.12711","article-title":"Measurement of transepidermal water loss, stratum corneum hydration and skin surface pH in occupational settings: A review","volume":"25","author":"Franken","year":"2019","journal-title":"Skin Res. Technol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/srt.12307","article-title":"Changes in hydration of the stratum corneum are the most suitable indicator to evaluate the irritation of surfactants on the skin","volume":"23","author":"Fujimura","year":"2017","journal-title":"Skin Res. Technol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jchromb.2015.01.009","article-title":"Development and validation of a high-performance liquid chromatography method for the quantification of ursolic\/oleanic acids mixture isolated from Plumeria obtusa","volume":"983\u2013984","author":"Alvarado","year":"2015","journal-title":"J. Chromatogr. B"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ejps.2016.12.030","article-title":"Analgesic and anti-inflammatory controlled-released injectable microemulsion: Pseudo-ternary phase diagrams, in vitro, ex vivo and in vivo evaluation","volume":"101","author":"Pineros","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1080\/01932691.2017.1391699","article-title":"Study on the relationship between emulsion stability and droplet dynamics of a spontaneous emulsion for chemical enhanced oil recovery","volume":"39","author":"Feng","year":"2018","journal-title":"J. Disper. Sci. Technol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.colsurfb.2012.10.061","article-title":"Transdermal delivery of imipramine and doxepin from newly oil-in-water nanoemulsions for an analgesic and anti-allodynic activity: Development, characterization and in vivo evaluation","volume":"103","author":"Sandig","year":"2013","journal-title":"Colloids Surf. B"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/12\/484\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:56Z","timestamp":1760179676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/12\/484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,21]]},"references-count":94,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ph13120484"],"URL":"https:\/\/doi.org\/10.3390\/ph13120484","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,21]]}}}