{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T17:05:26Z","timestamp":1769360726783,"version":"3.49.0"},"reference-count":70,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:00:00Z","timestamp":1606176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dr. Rolf M. Schwiete Stiftung Mannheim, Germany","award":["14\/2016"],"award-info":[{"award-number":["14\/2016"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) and Saarland University","award":["funding program Open Access Publishing"],"award-info":[{"award-number":["funding program Open Access Publishing"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Tofacitinib (TFB), a Janus kinase inhibitor, has shown excellent success off-label in treating various dermatological diseases, especially alopecia areata (AA). However, TFB\u2019s safe and targeted delivery into hair follicles (HFs) is highly desirable due to its systemic adverse effects. Nanoparticles (NPs) can enhance targeted follicular drug delivery and minimize interfollicular permeation and thereby reduce systemic drug exposure. In this study, we report a facile method to assemble the stable and uniform 240 nm TFB loaded squalenyl derivative (SqD) nanoparticles (TFB SqD NPs) in aqueous solution, which allowed an excellent loading capacity (LC) of 20%. The SqD NPs showed an enhanced TFB delivery into HFs compared to the aqueous formulations of plain drug in an ex vivo pig ear model. Furthermore, the therapeutic efficacy of the TFB SqD NPs was studied in a mouse model of allergic dermatitis by ear swelling reduction and compared to TFB dissolved in a non-aqueous mixture of acetone and DMSO (7:1 v\/v). Whereas such formulation would not be acceptable for use in the clinic, the TFB SqD NPs dispersed in water illustrated a better reduction in inflammatory effects than plain TFB\u2019s aqueous formulation, implying both encouraging good in vivo efficacy and safety. These findings support the potential of TFB SqD NPs for developing a long-term topical therapy of AA.<\/jats:p>","DOI":"10.3390\/pharmaceutics12121131","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T09:06:28Z","timestamp":1606208788000},"page":"1131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Tofacitinib Loaded Squalenyl Nanoparticles for Targeted Follicular Delivery in Inflammatory Skin Diseases"],"prefix":"10.3390","volume":"12","author":[{"given":"Rebekka","family":"Christmann","sequence":"first","affiliation":[{"name":"Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)\u2014Helmholtz Centre for Infection Research (HZI), 66123 Saarbr\u00fccken, Germany"},{"name":"Department of Pharmacy, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7327-6775","authenticated-orcid":false,"given":"Duy-Khiet","family":"Ho","sequence":"additional","affiliation":[{"name":"Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)\u2014Helmholtz Centre for Infection Research (HZI), 66123 Saarbr\u00fccken, Germany"},{"name":"Department of Pharmacy, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny","family":"Wilzopolski","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)\u2014Helmholtz Centre for Infection Research (HZI), 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Koch","sequence":"additional","affiliation":[{"name":"INM-Leibniz Institute for New Materials, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0057-5181","authenticated-orcid":false,"given":"Brigitta","family":"Loretz","sequence":"additional","affiliation":[{"name":"Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)\u2014Helmholtz Centre for Infection Research (HZI), 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Vogt","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Saarland University Hospital, 66421 Homburg\/Saar, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"B\u00e4umer","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-2168","authenticated-orcid":false,"given":"Ulrich F.","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus-Michael","family":"Lehr","sequence":"additional","affiliation":[{"name":"Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)\u2014Helmholtz Centre for Infection Research (HZI), 66123 Saarbr\u00fccken, Germany"},{"name":"Department of Pharmacy, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17011","DOI":"10.1038\/nrdp.2017.11","article-title":"Alopecia areata","volume":"3","author":"Pratt","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaad.2017.04.1141","article-title":"Alopecia areata: Disease characteristics, clinical evaluation, and new perspectives on pathogenesis","volume":"78","author":"Strazzulla","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/jid.2013.464","article-title":"Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009","volume":"134","author":"Mirzoyev","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bertolini, M., McElwee, K., Gilhar, A., Bulfone-Paus, S., and Paus, R. (2020). Hair follicle immune privilege and its collapse in alopecia areata. Exp. Dermatol.","DOI":"10.1111\/exd.14155"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0140-6736(18)32987-8","article-title":"JAK inhibitors and alopecia areata","volume":"393","author":"Gilhar","year":"2019","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jaad.2017.04.1142","article-title":"Alopecia areata: An appraisal of new treatment approaches and overview of current therapies","volume":"78","author":"Strazzulla","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1111\/jdv.13598","article-title":"Efficacy of tofacitinib in treatment of alopecia universalis in two patients","volume":"30","author":"Gupta","year":"2016","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1038\/jid.2014.260","article-title":"Killing two birds with one stone: Oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis","volume":"134","author":"Craiglow","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_9","unstructured":"FDA (2020, August 07). XELJANZ (Tofacitinib), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2018\/203214s018lbl.pdf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/nm.3685","article-title":"Inhibiting Janus kinases to treat alopecia areata","volume":"20","author":"Divito","year":"2014","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/nm.3645","article-title":"Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition","volume":"20","author":"Xing","year":"2014","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tegtmeyer, K., Zhao, J., Maloney, N.J., Atassi, G., Beestrum, M., and Lio, P.A. (2019). Off-label studies on tofacitinib in dermatology: A review. J. Dermatol. Treat., 1\u201311.","DOI":"10.1080\/09546634.2020.1755417"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.jaad.2016.12.004","article-title":"Janus kinase inhibitors in dermatology: A systematic review","volume":"76","author":"Ramot","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nrd.2017.201","article-title":"JAK inhibition as a therapeutic strategy for immune and inflammatory diseases","volume":"16","author":"Schwartz","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_15","first-page":"318","article-title":"The mechanism of action of tofacitinib\u2014An oral Janus kinase inhibitor for the treatment of rheumatoid arthritis","volume":"34","author":"Hodge","year":"2016","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_16","unstructured":"FDA Drug Safety Communication (2020, August 07). FDA Approves Boxed Warning about Increased Risk of Blood Clots and Death with Higher Dose of Arthritis and Ulcerative Colitis Medicine Tofacitinib (Xeljanz, Xeljanz XR), Available online: https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ebiom.2015.03.022","article-title":"Translational Positioning of Janus Kinase (JAK) Inhibitors in Alopecia Areata","volume":"2","author":"Vogt","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1039\/C7NR07706H","article-title":"Selective delivery of adapalene to the human hair follicle under finite dose conditions using polymeric micelle nanocarriers","volume":"10","author":"Kandekar","year":"2018","journal-title":"Nanoscale"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.nano.2014.08.009","article-title":"Efficient nanoparticle-mediated needle-free transcutaneous vaccination via hair follicles requires adjuvantation","volume":"11","author":"Mittal","year":"2015","journal-title":"Nanomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ejpb.2006.10.019","article-title":"Nanoparticles\u2014An efficient carrier for drug delivery into the hair follicles","volume":"66","author":"Lademann","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1159\/000093119","article-title":"Hair follicles\u2014A long-term reservoir for drug delivery","volume":"19","author":"Lademann","year":"2006","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jconrel.2015.12.010","article-title":"Nanocarriers for optimizing the balance between interfollicular permeation and follicular uptake of topically applied clobetasol to minimize adverse effects","volume":"223","author":"Mathes","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1159\/000354921","article-title":"Nanoencapsulation in lipid-core nanocapsules controls mometasone furoate skin permeability rate and its penetration to the deeper skin layers","volume":"27","author":"Melero","year":"2014","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.jconrel.2016.09.015","article-title":"Do nanoparticles have a future in dermal drug delivery?","volume":"246","author":"Patzelt","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ejpb.2016.10.005","article-title":"Ratchet effect for nanoparticle transport in hair follicles","volume":"116","author":"Radtke","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.jid.2019.05.028","article-title":"Nanoparticle Targeting to Scalp Hair Follicles: New Perspectives for a Topical Therapy for Alopecia Areata","volume":"140","author":"Christmann","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-L\u00f3pez, E., Gomes, D., Esteruelas, G., Bonilla, L., Lopez-Machado, A.L., Galindo, R., Cano, A., Espina, M., Ettcheto, M., and Camins, A. (2020). Metal-Based Nanoparticles as Antimicrobial Agents: An Overview. Nanomaterials, 10.","DOI":"10.3390\/nano10020292"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jconrel.2016.12.022","article-title":"Topical and cutaneous delivery using nanosystems","volume":"247","author":"Roberts","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.actbio.2015.11.052","article-title":"Triggered release of model drug from AuNP-doped BSA nanocarriers in hair follicles using IRA radiation","volume":"30","author":"Lademann","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1246\/bcsj.20190346","article-title":"Ultrasound-Activated Nanomaterials for Therapeutics","volume":"93","author":"Paris","year":"2020","journal-title":"BCSJ"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ejpb.2019.09.002","article-title":"Challenges and strategies in drug delivery systems for treatment of pulmonary infections","volume":"144","author":"Ho","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.addr.2012.04.010","article-title":"Nanoparticles in drug delivery: Past, present and future","volume":"65","author":"Couvreur","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_33","unstructured":"Yichuan, Z. (2019). Lipid Nanoparticle-Mediated Delivery of Enhanced Costimulation Blockade to Prevent Type 1 Diabetes. [Master of Science, Master\u2019s Thesis, Johns Hopkins University]."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bashir, S., Aamir, M., Sarfaraz, R.M., Hussain, Z., Sarwer, M.U., Mahmood, A., Akram, M.R., and Qaisar, M.N. (2020). Fabrication, characterization and in vitro release kinetics of tofacitinib-encapsulated polymeric nanoparticles: A promising implication in the treatment of rheumatoid arthritis. Int. J. Polym. Mater. Polym. Biomater., 1\u201310.","DOI":"10.1080\/00914037.2020.1725760"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1194\/jlr.R700015-JLR200","article-title":"Thematic review series: Skin lipids. Sebaceous gland lipids: Friend or foe?","volume":"49","author":"Smith","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.addr.2009.09.005","article-title":"Squalene: A natural triterpene for use in disease management and therapy","volume":"61","author":"Reddy","year":"2009","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1021\/nl061942q","article-title":"Squalenoyl nanomedicines as potential therapeutics","volume":"6","author":"Couvreur","year":"2006","journal-title":"Nano Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.jconrel.2011.07.038","article-title":"Squalenoylation: A generic platform for nanoparticular drug delivery","volume":"161","author":"Gref","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3456","DOI":"10.1021\/acs.molpharmaceut.8b00433","article-title":"Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis","volume":"15","author":"Wei","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jpba.2017.05.012","article-title":"Identification of related substances in tofacitinib citrate by LC-MS techniques for synthetic process optimization","volume":"143","author":"Wu","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1208\/s12249-019-1377-0","article-title":"Preformulation and Evaluation of Tofacitinib as a Therapeutic Treatment for Asthma","volume":"20","author":"Younis","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jconrel.2014.07.060","article-title":"Novel self assembling nanoparticles for the oral administration of fondaparinux: Synthesis, characterization and in vivo evaluation","volume":"194","author":"Bianchini","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10292","DOI":"10.1002\/anie.202001407","article-title":"Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections","volume":"59","author":"Ho","year":"2020","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ho, D.-K., Christmann, R., Murgia, X., de Rossi, C., Frisch, S., Koch, M., Schaefer, U.F., Loretz, B., Desma\u00eble, D., and Couvreur, P. (2020). Synthesis and biopharmaceutical characterization of amphiphilic squalenyl derivatives based versatile drug delivery platform. Front. Chem.","DOI":"10.3389\/fchem.2020.584242"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jconrel.2014.01.018","article-title":"Quantification of nanoparticle uptake into hair follicles in pig ear and human forearm","volume":"179","author":"Raber","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18651","DOI":"10.1039\/C5NR04770F","article-title":"Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle","volume":"7","author":"Lapteva","year":"2015","journal-title":"Nanoscale"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1124\/jpet.115.223784","article-title":"Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis","volume":"354","author":"Fukuyama","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1600-0536.2007.01138.x","article-title":"Biophysical parameters of skin: Map of human face, regional, and age-related differences","volume":"57","author":"Marrakchi","year":"2007","journal-title":"Contact Dermat."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.ejpb.2009.02.003","article-title":"Comparison of two in vitro models for the analysis of follicular penetration and its prevention by barrier emulsions","volume":"72","author":"Lademann","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ejpb.2008.02.024","article-title":"Differential stripping demonstrates a significant reduction of the hair follicle reservoir in vitro compared to in vivo","volume":"70","author":"Patzelt","year":"2008","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1159\/000257263","article-title":"Which skin model is the most appropriate for the investigation of topically applied substances into the hair follicles?","volume":"23","author":"Lademann","year":"2010","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_52","first-page":"e04873","article-title":"Guidance on dermal absorption","volume":"15","author":"Buist","year":"2017","journal-title":"EFSA J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.0022-202X.2005.23779.x","article-title":"Differential stripping: Determination of the amount of topically applied substances penetrated into the hair follicles","volume":"125","author":"Teichmann","year":"2005","journal-title":"J. Investig. Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1080\/09546634.2018.1527997","article-title":"Should we instruct patients to rub topical agents into skin? The evidence","volume":"30","author":"Li","year":"2019","journal-title":"J. Dermatol. Treat."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Dragicevic, N.I., and Maibach, H. (2017). Stripping Procedures for Penetration Measurements of Topically Applied Substances. Percutaneous Penetration Enhancers Drug Penetration Into\/Through the Skin: Methodology and General Considerations, Springer.","DOI":"10.1007\/978-3-662-53270-6"},{"key":"ref_56","unstructured":"FDA\/CDER (2020, August 07). Bioanalytical Method Validation Guidance for Industry, Available online: https:\/\/www.fda.gov\/files\/drugs\/published\/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/j.1365-2133.2004.06220.x","article-title":"TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines","volume":"151","author":"Seegers","year":"2004","journal-title":"Br. J. Dermatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.ejphar.2003.09.031","article-title":"Effects of cilomilast on dendritic cell function in contact sensitivity and dendritic cell migration through skin","volume":"481","author":"Tschernig","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1159\/000094670","article-title":"The pH of the skin surface and its impact on the barrier function","volume":"19","author":"Korting","year":"2006","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_60","unstructured":"Committee for Medicinal Products for Human Use (2020, September 15). Assessment Report: Xeljanz; INN-Tofacitinib. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/xeljanz-epar-public-assessment-report_en-0.pdf."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jconrel.2016.06.017","article-title":"DLS and zeta potential\u2014What they are and what they are not?","volume":"235","author":"Bhattacharjee","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0021-9258(18)86000-8","article-title":"A buffer solution for colorimetric comparison","volume":"49","author":"McIlvaine","year":"1921","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1600505","DOI":"10.1002\/mabi.201600505","article-title":"Synthesis and Validation of Functional Nanogels as pH-Sensors in the Hair Follicle","volume":"17","author":"Dimde","year":"2017","journal-title":"Macromol. Biosci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kaden, D., D\u00e4hne, L., Knorr, F., Richter, H., Lademann, J., Meinke, M.C., Patzelt, A., Darvin, M.E., and Jung, S. (2020). Determination of the pH Gradient in Hair Follicles of Human Volunteers Using pH-Sensitive Melamine Formaldehyde-Pyranine Nile Blue Microparticles. Sensors, 20.","DOI":"10.3390\/s20185243"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/j.1365-2125.2007.03065.x","article-title":"The role of hair follicles in the percutaneous absorption of caffeine","volume":"65","author":"Otberg","year":"2008","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_66","unstructured":"Scientific Committee on Consumer Safety SCCS (2020, July 08). The Sccs Notes of Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation 10th Revision. Available online: https:\/\/ec.europa.eu\/health\/sites\/health\/files\/scientific_committees\/consumer_safety\/docs\/sccs_o_224.pdf."},{"key":"ref_67","first-page":"1107","article-title":"AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis","volume":"55","author":"Gorr","year":"2003","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4641","DOI":"10.1038\/s41598-019-40660-0","article-title":"DMSO induces drastic changes in human cellular processes and epigenetic landscape in vitro","volume":"9","author":"Verheijen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.addr.2012.09.032","article-title":"Penetration enhancers","volume":"64","author":"Williams","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8035","DOI":"10.2147\/IJN.S139139","article-title":"Confocal laser scanning microscopy to estimate nanoparticles\u2019 human skin penetration in vitro","volume":"12","author":"Zou","year":"2017","journal-title":"Int. J. Nanomed."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/12\/1131\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:36:29Z","timestamp":1760178989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/12\/1131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":70,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["pharmaceutics12121131"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12121131","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,24]]}}}