Owing to their complicated pathophysiology, the treatment of skin diseases necessitates a complex approach. Conventional treatment using topical corticosteroids often results in low effectiveness and the incidence of local or even systemic side effects. Nanoformulation of potent anti-inflammatory drugs has been selected as an optimal strategy for enhanced topical delivery of corticosteroids. In order to assess the efficiency of various nanoformulations, we formulated hydrocortisone (HC) and hydrocortisone-17-butyrate (HCB) into three different systems: lipid nanocapsules (LNC), polymeric nanoparticles (PNP), and ethosomes (ETZ). The systems were characterized using dynamic light scattering for their particle size and uniformity and the morphology of nanoparticles was observed by transmission electron microscopy. The nanosystems were tested using ex vivo full thickness porcine and human skin for the delivery of HC and HCB. The skin penetration was observed by confocal microscopy of fluorescently labelled nanosystems. ETZ were proposed as the most effective delivery system for both transdermal and dermal drug targeting but were also found to have a profound effect on the skin barrier with limited restoration. LNC and PNP were found to have significant effects in the dermal delivery of the actives with only minimal transdermal penetration, especially in case of HCB administration.

Center for Dermal Research Life Sciences Building Rutgers University Piscataway NJ 08854 USA

Department of Organic Technology Faculty of Chemical Technology University of Chemistry and Technology Prague Technická 5 166 28 Prague Czech Republic

Department of Pharmaceutical Technology Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

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Hadi H.A., Tarmizi A.I., Khalid K.A., Gajdács M., Aslam A., Jamshed S. The Epidemiology and Global Burden of Atopic Dermatitis: A Narrative Review. Life. 2021;11:936. doi: 10.3390/life11090936. PubMed DOI PMC

Siddique M.I., Katas H., Amin M.C.I.M., Ng S.-F., Zulfakar M.H., Buang F., Jamil A. Minimization of Local and Systemic Adverse Effects of Topical Glucocorticoids by Nanoencapsulation: In Vivo Safety of Hydrocortisone;Hydroxytyrosol Loaded Chitosan Nanoparticles. J. Pharm. Sci. 2015;104:4276–4286. doi: 10.1002/jps.24666. PubMed DOI

Boguniewicz M., Leung D.Y. Atopic dermatitis: A disease of altered skin barrier and immune dysregulation. Immunol. Rev. 2011;242:233–246. doi: 10.1111/j.1600-065X.2011.01027.x. PubMed DOI PMC

Wolf R., Wolf D. Abnormal epidermal barrier in the pathogenesis of atopic dermatitis. Clin. Dermatol. 2012;30:329–334. doi: 10.1016/j.clindermatol.2011.08.023. PubMed DOI

Beattie P.E., Lewis-Jones M.S. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br. J. Dermatol. 2006;155:145–151. doi: 10.1111/j.1365-2133.2006.07185.x. PubMed DOI

Guo J.W., Jee S.H. Strategies to Develop a Suitable Formulation for Inflammatory Skin Disease Treatment. Int. J. Mol. Sci. 2021;22:6078. doi: 10.3390/ijms22116078. PubMed DOI PMC

Ring J., Alomar A., Bieber T., Deleuran M., Fink-Wagner A., Gelmetti C., Gieler U., Lipozencic J., Luger T., Oranje A.P., et al. Guidelines for treatment of atopic eczema (atopic dermatitis) Part I. J. Eur. Acad. Dermatol. Venereol. 2012;26:1045–1060. doi: 10.1111/j.1468-3083.2012.04635.x. PubMed DOI

Kalvodová A., Zbytovská J. Lipid nanocapsules enhance the transdermal delivery of drugs regardless of their physico-chemical properties. Int. J. Pharm. 2022;628:122264. doi: 10.1016/j.ijpharm.2022.122264. PubMed DOI

Čuříková-Kindlová B.A., Vovesná A., Nováčková A., Zbytovská J. In Vitro Modeling of Skin Barrier Disruption and its Recovery by Ceramide-Based Formulations. AAPS PharmSciTech. 2021;23:21. doi: 10.1208/s12249-021-02154-z. PubMed DOI

Axon E., Chalmers J.R., Santer M., Ridd M.J., Lawton S., Langan S.M., Grindlay D.J.C., Muller I., Roberts A., Ahmed A., et al. Safety of topical corticosteroids in atopic eczema: An umbrella review. BMJ Open. 2021;11:e046476. doi: 10.1136/bmjopen-2020-046476. PubMed DOI PMC

Goa K.L. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs. 1988;36((Suppl. S5)):51–61. doi: 10.2165/00003495-198800365-00011. PubMed DOI

Buys L.M. Treatment options for atopic dermatitis. Am. Fam. Physician. 2007;75:523–528. PubMed

Ference J.D., Last A.R. Choosing topical corticosteroids. Am. Fam. Physician. 2009;79:135–140. PubMed

Draelos Z.D. Use of topical corticosteroids and topical calcineurin inhibitors for the treatment of atopic dermatitis in thin and sensitive skin areas. Curr. Med. Res. Opin. 2008;24:985–994. doi: 10.1185/030079908X280419. PubMed DOI

Li A.W., Yin E.S., Antaya R.J. Topical Corticosteroid Phobia in Atopic Dermatitis: A Systematic Review. JAMA Dermatol. 2017;153:1036–1042. doi: 10.1001/jamadermatol.2017.2437. PubMed DOI

Schimmer B.P., Funder J.W. Adrenocorticotropic Hormone, Adrenal Steroids, and the Adrenal Cortex. In: Brunton L.L., Hilal-Dandan R., Knollmann B.C., editors. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. McGraw-Hill Education; New York, NY, USA: 2017.

Goodwin J.S., Atluru D., Sierakowski S., Lianos E.A. Mechanism of action of glucocorticosteroids. Inhibition of T cell proliferation and interleukin 2 production by hydrocortisone is reversed by leukotriene B4. J. Clin. Investig. 1986;77:1244–1250. doi: 10.1172/JCI112427. PubMed DOI PMC

Cevc G., Blume G., Schätzlein A. Transfersomes-mediated transepidermal delivery improves the regio-specificity and biological activity of corticosteroids in vivo. J. Control. Release. 1997;45:211–226. doi: 10.1016/S0168-3659(96)01566-0. DOI

Gee C.M., Nicolazzo J.A., Watkinson A.C., Finnin B.C. Assessment of the Lateral Diffusion and Penetration of Topically Applied Drugs in Humans Using a Novel Concentric Tape Stripping Design. Pharm. Res. 2012;29:2035–2046. doi: 10.1007/s11095-012-0731-7. PubMed DOI

Shetty K., Sherje A.P. Nano intervention in topical delivery of corticosteroid for psoriasis and atopic dermatitis-a systematic review. J. Mater. Sci. Mater. Med. 2021;32:88. doi: 10.1007/s10856-021-06558-y. PubMed DOI PMC

Hemrajani C., Negi P., Parashar A., Gupta G., Jha N.K., Singh S.K., Chellappan D.K., Dua K. Overcoming drug delivery barriers and challenges in topical therapy of atopic dermatitis: A nanotechnological perspective. Biomed. Pharmacother. 2022;147:112633. doi: 10.1016/j.biopha.2022.112633. PubMed DOI

Kim M.K., Chung S.J., Lee M.H., Cho A.R., Shim C.K. Targeted and sustained delivery of hydrocortisone to normal and stratum corneum-removed skin without enhanced skin absorption using a liposome gel. J. Control. Release. 1997;46:243–251. doi: 10.1016/S0168-3659(96)01604-5. DOI

Attama A.A., Weber C., Müller-Goymann C.C. Assessment of drug permeation from lipid nanoparticles formulated with a novel structured lipid matrix through artificial skin construct bio-engineered from HDF and HaCaT cell lines. J. Drug Deliv. Sci. Technol. 2008;18:181–188. doi: 10.1016/S1773-2247(08)50034-7. DOI

Cavalli R., Peira E., Caputo O., Gasco M.R. Solid lipid nanoparticles as carriers of hydrocortisone and progesterone complexes with beta-cyclodextrins. Int. J. Pharm. 1999;182:59–69. doi: 10.1016/S0378-5173(99)00066-6. PubMed DOI

Mombeiny R., Tavakol S., Kazemi M., Mehdizadeh M., Hasanzadeh A., Karimi Babaahmadi M., Abedi A., Keyhanvar P. Anti-inflammatory ethosomal nanoformulation in combination with iontophoresis in chronic wound healing: An ex vivo study. IET Nanobiotechnol. 2021;15:710–718. doi: 10.1049/nbt2.12069. PubMed DOI PMC

Yang X., Patel S., Sheng Y., Pal D., Mitra A.K. Statistical design for formulation optimization of hydrocortisone butyrate-loaded PLGA nanoparticles. AAPS PharmSciTech. 2014;15:569–587. doi: 10.1208/s12249-014-0072-4. PubMed DOI PMC

Alvarez-Figueroa M.J., Alarcón D.A., González-Aramúndiz J.V. Effect of zeta potential of innovative lipid nanocapsules on triamcinolone transdermal delivery. Drug Deliv. Transl. Res. 2022;12:2740–2750. doi: 10.1007/s13346-022-01134-5. PubMed DOI

El-Sheridy N.A., Ramadan A.A., Eid A.A., El-Khordagui L.K. Itraconazole lipid nanocapsules gel for dermatological applications: In vitro characteristics and treatment of induced cutaneous candidiasis. Colloids Surf. B Biointerfaces. 2019;181:623–631. doi: 10.1016/j.colsurfb.2019.05.057. PubMed DOI

Luengo J., Schneider M., Schneider A.M., Lehr C.-M., Schaefer U.F. Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes. Pharmaceutics. 2021;13:1608. doi: 10.3390/pharmaceutics13101608. PubMed DOI PMC

Md S., Alhakamy N.A., Neamatallah T., Alshehri S., Mujtaba M.A., Riadi Y., Radhakrishnan A.K., Khalilullah H., Gupta M., Akhter M.H. Development, Characterization, and Evaluation of α -Mangostin-Loaded Polymeric Nanoparticle Gel for Topical Therapy in Skin Cancer. Gels. 2021;7:230. doi: 10.3390/gels7040230. PubMed DOI PMC

Takeuchi I., Kagawa A., Makino K. Skin permeability and transdermal delivery route of 30-nm cyclosporin A-loaded nanoparticles using PLGA-PEG-PLGA triblock copolymer. Colloids Surf. A Physicochem. Eng. Asp. 2020;600:124866. doi: 10.1016/j.colsurfa.2020.124866. DOI

Abd El-Alim S.H., Kassem A.A., Basha M., Salama A. Comparative study of liposomes, ethosomes and transfersomes as carriers for enhancing the transdermal delivery of diflunisal: In vitro and in vivo evaluation. Int. J. Pharm. 2019;563:293–303. doi: 10.1016/j.ijpharm.2019.04.001. PubMed DOI

Nair R.S., Billa N., Leong C.-O., Morris A.P. An evaluation of tocotrienol ethosomes for transdermal delivery using Strat-M® membrane and excised human skin. Pharm. Dev. Technol. 2021;26:243–251. doi: 10.1080/10837450.2020.1860087. PubMed DOI

Heurtault B., Saulnier P., Pech B., Proust J.E., Benoit J.P. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm. Res. 2002;19:875–880. doi: 10.1023/A:1016121319668. PubMed DOI

Huynh N.T., Passirani C., Saulnier P., Benoit J.P. Lipid nanocapsules: A new platform for nanomedicine. Int. J. Pharm. 2009;379:201–209. doi: 10.1016/j.ijpharm.2009.04.026. PubMed DOI

Fessi H., Puisieux F., Devissaguet J.P., Ammoury N., Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int. J. Pharm. 1989;55:R1–R4. doi: 10.1016/0378-5173(89)90281-0. DOI

Touitou E., Dayan N., Bergelson L., Godin B., Eliaz M. Ethosomes-novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. J. Control. Release. 2000;65:403–418. doi: 10.1016/S0168-3659(99)00222-9. PubMed DOI

Touitou E., Godin B. Ethosomes for skin delivery. J. Drug Deliv. Sci. Technol. 2007;17:303–308. doi: 10.1016/S1773-2247(07)50046-8. DOI

Alvarado J.F., Rozo D.F., Chaparro L.M., Medina J.A., Salcedo-Galán F. Synthesis and Characterization of Reproducible Linseed Oil-Loaded Silica Nanoparticles with Potential Use as Oxygen Scavengers in Active Packaging. Nanomaterials. 2022;12:3257. doi: 10.3390/nano12183257. PubMed DOI PMC

Weiss B., Schaefer U.F., Zapp J., Lamprecht A., Stallmach A., Lehr C.M. Nanoparticles made of fluorescence-labelled Poly(L-lactide-co-glycolide): Preparation, stability, and biocompatibility. J. Nanosci. Nanotechnol. 2006;6:3048–3056. doi: 10.1166/jnn.2006.424. PubMed DOI

Christmann R., Ho D.K., Wilzopolski J., Lee S., Koch M., Loretz B., Vogt T., Bäumer W., Schaefer U.F., Lehr C.M. Tofacitinib Loaded Squalenyl Nanoparticles for Targeted Follicular Delivery in Inflammatory Skin Diseases. Pharmaceutics. 2020;12:1131. doi: 10.3390/pharmaceutics12121131. PubMed DOI PMC

El-Leithy E.S., Abdel-Rashid R.S. Lipid nanocarriers for tamoxifen citrate/coenzyme Q10 dual delivery. J. Drug Deliv. Sci. Technol. 2017;41:239–250. doi: 10.1016/j.jddst.2017.07.020. DOI

Čuříková B.A., Procházková K., Filková B., Diblíková P., Svoboda J., Kováčik A., Vávrová K., Zbytovská J. Simplified stratum corneum model membranes for studying the effects of permeation enhancers. Int. J. Pharm. 2017;534:287–296. doi: 10.1016/j.ijpharm.2017.10.038. PubMed DOI

Dvořáková K., Štěpánek P., Kroupová J., Zbytovská J. N-Alkylmorpholines: Potent Dermal and Transdermal Skin Permeation Enhancers. Pharmaceutics. 2021;14:64. doi: 10.3390/pharmaceutics14010064. PubMed DOI PMC

Elkeeb R., Hui X., Chan H., Tian L., Maibach H.I. Correlation of transepidermal water loss with skin barrier properties in vitro: Comparison of three evaporimeters. Ski. Res. Technol. 2010;16:9–15. doi: 10.1111/j.1600-0846.2009.00406.x. PubMed DOI

Pinnagoda J., Tupkek R.A., Agner T., Serup J. Guidelines for transepidermal water loss (TEWL) measurement. Contact Dermat. 1990;22:164–178. doi: 10.1111/j.1600-0536.1990.tb01553.x. PubMed DOI

Das S., Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech. 2011;12:62–76. doi: 10.1208/s12249-010-9563-0. PubMed DOI PMC

Freitas C., Müller R.H. Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN™) dispersions. Int. J. Pharm. 1998;168:221–229. doi: 10.1016/S0378-5173(98)00092-1. DOI

Manconi M., Aparicio J., Vila A.O., Pendás J., Figueruelo J., Molina F. Viscoelastic properties of concentrated dispersions in water of soy lecithin. Colloids Surf. A Physicochem. Eng. Asp. 2003;222:141–145. doi: 10.1016/S0927-7757(03)00249-8. DOI

Stipa P., Marano S., Galeazzi R., Minnelli C., Mobbili G., Laudadio E. Prediction of drug-carrier interactions of PLA and PLGA drug-loaded nanoparticles by molecular dynamics simulations. Eur. Polym. J. 2021;147:110292. doi: 10.1016/j.eurpolymj.2021.110292. PubMed DOI PMC

Holzer M., Vogel V., Mäntele W., Schwartz D., Haase W., Langer K. Physico-chemical characterisation of PLGA nanoparticles after freeze-drying and storage. Eur. J. Pharm. Biopharm. 2009;72:428–437. doi: 10.1016/j.ejpb.2009.02.002. PubMed DOI

Govender T., Stolnik S., Garnett M.C., Illum L., Davis S.S. PLGA nanoparticles prepared by nanoprecipitation: Drug loading and release studies of a water soluble drug. J. Control. Release. 1999;57:171–185. doi: 10.1016/S0168-3659(98)00116-3. PubMed DOI

Budhian A., Siegel S.J., Winey K.I. Haloperidol-loaded PLGA nanoparticles: Systematic study of particle size and drug content. Int. J. Pharm. 2007;336:367–375. doi: 10.1016/j.ijpharm.2006.11.061. PubMed DOI

Sahoo S.K., Panyam J., Prabha S., Labhasetwar V. Residual polyvinyl alcohol associated with poly (d, l-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake. J. Control. Release. 2002;82:105–114. doi: 10.1016/S0168-3659(02)00127-X. PubMed DOI

Ascenso A., Raposo S., Batista C., Cardoso P., Mendes T., Praça F.G., Bentley M.V., Simões S. Development, characterization, and skin delivery studies of related ultradeformable vesicles: Transfersomes, ethosomes, and transethosomes. Int. J. Nanomed. 2015;10:5837–5851. doi: 10.2147/IJN.S86186. PubMed DOI PMC

Brasili F., Capocefalo A., Palmieri D., Capitani F., Chiessi E., Paradossi G., Bordi F., Domenici F. Assembling patchy plasmonic nanoparticles with aggregation-dependent antibacterial activity. J. Colloid Interface Sci. 2020;580:419–428. doi: 10.1016/j.jcis.2020.07.006. PubMed DOI

Kumari S., Pathak K. Cavamax W7 composite psoralen ethosomal gel versus cavamax W7 psoralen solid complex gel for topical delivery: A comparative evaluation. Int. J. Pharm. Investig. 2013;3:171–182. doi: 10.4103/2230-973x.121284. PubMed DOI PMC

Yasar H., Biehl A., De Rossi C., Koch M., Murgia X., Loretz B., Lehr C.-M. Kinetics of mRNA delivery and protein translation in dendritic cells using lipid-coated PLGA nanoparticles. J. Nanobiotechnol. 2018;16:72. doi: 10.1186/s12951-018-0401-y. PubMed DOI PMC

Fonte P., Soares S., Sousa F., Costa A., Seabra V., Reis S., Sarmento B. Stability Study Perspective of the Effect of Freeze-Drying Using Cryoprotectants on the Structure of Insulin Loaded into PLGA Nanoparticles. Biomacromolecules. 2014;15:3753–3765. doi: 10.1021/bm5010383. PubMed DOI

Balzus B., Sahle F.F., Hönzke S., Gerecke C., Schumacher F., Hedtrich S., Kleuser B., Bodmeier R. Formulation and ex vivo evaluation of polymeric nanoparticles for controlled delivery of corticosteroids to the skin and the corneal epithelium. Eur. J. Pharm. Biopharm. 2017;115:122–130. doi: 10.1016/j.ejpb.2017.02.001. PubMed DOI

Eroğlu İ., Azizoğlu E., Özyazıcı M., Nenni M., Gürer Orhan H., Özbal S., Tekmen I., Ertam İ., Ünal İ., Özer Ö. Effective topical delivery systems for corticosteroids: Dermatological and histological evaluations. Drug Deliv. 2016;23:1502–1513. doi: 10.3109/10717544.2014.960981. PubMed DOI

Kong W., Salim N., Masoumi H.R.F., Basri M., Da Costa S.S., Ahmad N. Optimization of Hydrocortisone-Loaded Nanoemulsion Formulation Using D-Optimal Mixture Design. Asian J. Chem. 2018;30:853–858. doi: 10.14233/ajchem.2018.21104. DOI

Yang X., Trinh H.M., Agrahari V., Sheng Y., Pal D., Mitra A.K. Nanoparticle-Based Topical Ophthalmic Gel Formulation for Sustained Release of Hydrocortisone Butyrate. AAPS PharmSciTech. 2016;17:294–306. doi: 10.1208/s12249-015-0354-5. PubMed DOI PMC

Lademann J., Knorr F., Richter H., Blume-Peytavi U., Vogt A., Antoniou C., Sterry W., Patzelt A. Hair Follicles—An Efficient Storage and Penetration Pathway for Topically Applied Substances. Ski. Pharmacol. Physiol. 2008;21:150–155. doi: 10.1159/000131079. PubMed DOI

Schoepe S., Schäcke H., May E., Asadullah K. Glucocorticoid therapy-induced skin atrophy. Exp. Dermatol. 2006;15:406–420. doi: 10.1111/j.0906-6705.2006.00435.x. PubMed DOI

Caussin J., Gooris G.S., Janssens M., Bouwstra J.A. Lipid organization in human and porcine stratum corneum differs widely, while lipid mixtures with porcine ceramides model human stratum corneum lipid organization very closely. Biochim. Biophys. Acta (BBA)-Biomembr. 2008;1778:1472–1482. doi: 10.1016/j.bbamem.2008.03.003. PubMed DOI

Sinico C., Manconi M., Peppi M., Lai F., Valenti D., Fadda A.M. Liposomes as carriers for dermal delivery of tretinoin: In vitro evaluation of drug permeation and vesicle-skin interaction. J. Control. Release. 2005;103:123–136. doi: 10.1016/j.jconrel.2004.11.020. PubMed DOI

Feldmann R.J., Maibach H.I. Penetration of 14C Hydrocortisone Through Normal Skin: The Effect of Stripping and Occlusion. Arch. Dermatol. 1965;91:661–666. doi: 10.1001/archderm.1965.01600120093023. PubMed DOI

Megrab N.A., Williams A.C., Barry B.W. Oestradiol permeation through human skin and silastic membrane: Effects of propylene glycol and supersaturation. J. Control. Release. 1995;36:277–294. doi: 10.1016/0168-3659(95)00062-D. DOI

Vovesná A., Zhigunov A., Balouch M., Zbytovská J. Ceramide liposomes for skin barrier recovery: A novel formulation based on natural skin lipids. Int. J. Pharm. 2021;596:120264. doi: 10.1016/j.ijpharm.2021.120264. PubMed DOI

Algiert-Zielińska B., Batory M., Skubalski J., Rotsztejn H. Evaluation of the relation between lipid coat, transepidermal water loss, and skin pH. Int. J. Dermatol. 2017;56:1192–1197. doi: 10.1111/ijd.13726. PubMed DOI

Netzlaff F., Kostka K.H., Lehr C.M., Schaefer U.F. TEWL measurements as a routine method for evaluating the integrity of epidermis sheets in static Franz type diffusion cells in vitro. Limitations shown by transport data testing. Eur. J. Pharm. Biopharm. 2006;63:44–50. doi: 10.1016/j.ejpb.2005.10.009. PubMed DOI

Fluhr J.W., Feingold K.R., Elias P.M. Transepidermal water loss reflects permeability barrier status: Validation in human and rodent in vivo and ex vivo models. Exp. Dermatol. 2006;15:483–492. doi: 10.1111/j.1600-0625.2006.00437.x. PubMed DOI

Zhang Q., Murawsky M., LaCount T., Kasting G.B., Li S.K. Transepidermal water loss and skin conductance as barrier integrity tests. Toxicol Vitr. 2018;51:129–135. doi: 10.1016/j.tiv.2018.04.009. PubMed DOI PMC

Kopečná M., Macháček M., Prchalová E., Štěpánek P., Drašar P., Kotora M., Vávrová K. Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids. Pharm. Res. 2017;34:640–653. doi: 10.1007/s11095-016-2093-z. PubMed DOI

Kong R., Bhargava R. Characterization of porcine skin as a model for human skin studies using infrared spectroscopic imaging. Analyst. 2011;136:2359–2366. doi: 10.1039/c1an15111h. PubMed DOI

Čuříková-Kindlová B.A., Diat O., Štěpánek F., Vávrová K., Zbytovská J. Probing the interactions among sphingosine and phytosphingosine ceramides with non- and alpha-hydroxylated acyl chains in skin lipid model membranes. Int. J. Pharm. 2019;563:384–394. doi: 10.1016/j.ijpharm.2019.04.010. PubMed DOI

Kopečná M., Macháček M., Nováčková A., Paraskevopoulos G., Roh J., Vávrová K. Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers. Sci. Rep. 2019;9:14617. doi: 10.1038/s41598-019-51226-5. PubMed DOI PMC

Raber A.S., Mittal A., Schäfer J., Bakowsky U., Reichrath J., Vogt T., Schaefer U.F., Hansen S., Lehr C.M. Quantification of nanoparticle uptake into hair follicles in pig ear and human forearm. J. Control. Release. 2014;179:25–32. doi: 10.1016/j.jconrel.2014.01.018. PubMed DOI

Zhang Z., Tsai P.C., Ramezanli T., Michniak-Kohn B.B. Polymeric nanoparticles-based topical delivery systems for the treatment of dermatological diseases. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2013;5:205–218. doi: 10.1002/wnan.1211. PubMed DOI PMC

Knorr F., Lademann J., Patzelt A., Sterry W., Blume-Peytavi U., Vogt A. Follicular transport route–Research progress and future perspectives. Eur. J. Pharm. Biopharm. 2009;71:173–180. doi: 10.1016/j.ejpb.2008.11.001. PubMed DOI

Godin B., Touitou E. Ethosomes: New prospects in transdermal delivery. Crit. Rev. Ther. Drug Carr. Syst. 2003;20:63–102. doi: 10.1615/CritRevTherDrugCarrierSyst.v20.i1.20. PubMed DOI

Raszewska-Famielec M., Flieger J. Nanoparticles for Topical Application in the Treatment of Skin Dysfunctions—An Overview of Dermo-Cosmetic and Dermatological Products. Int. J. Mol. Sci. 2022;23:5980. doi: 10.3390/ijms232415980. PubMed DOI PMC

Souto E.B., Fangueiro J.F., Fernandes A.R., Cano A., Sanchez-Lopez E., Garcia M.L., Severino P., Paganelli M.O., Chaud M.V., Silva A.M. Physicochemical and biopharmaceutical aspects influencing skin permeation and role of SLN and NLC for skin drug delivery. Heliyon. 2022;8:e08938. doi: 10.1016/j.heliyon.2022.e08938. PubMed DOI PMC

Tiwari N., Osorio-Blanco E.R., Sonzogni A., Esporrín-Ubieto D., Wang H., Calderón M. Nanocarriers for Skin Applications: Where Do We Stand? Angew. Chem. Int. Ed. 2022;61:e202107960. doi: 10.1002/anie.202107960. PubMed DOI PMC

Paiva-Santos A.C., Silva A.L., Guerra C., Peixoto D., Pereira-Silva M., Zeinali M., Mascarenhas-Melo F., Castro R., Veiga F. Ethosomes as Nanocarriers for the Development of Skin Delivery Formulations. Pharm. Res. 2021;38:947–970. doi: 10.1007/s11095-021-03053-5. PubMed DOI

Lin H., Lin L., Choi Y., Michniak-Kohn B. Development and in-vitro evaluation of co-loaded berberine chloride and evodiamine ethosomes for treatment of melanoma. Int. J. Pharm. 2020;581:119278. doi: 10.1016/j.ijpharm.2020.119278. PubMed DOI

Todo H. Transdermal Permeation of Drugs in Various Animal Species. Pharmaceutics. 2017;9:33. doi: 10.3390/pharmaceutics9030033. PubMed DOI PMC

Vecchia B., Bunge A. Dermal Absorption Models in Toxicology and Pharmacology. CRC Taylor & Francis; Boca Raton, FL, USA: 2005. Animal Models: A Comparison of Permeability Coefficients for Excised Skin from Humans and Animals; pp. 305–367.

Laugel C., Baillet A., Youenang Piemi M.P., Marty J.P., Ferrier D. Oil–water–oil multiple emulsions for prolonged delivery of hydrocortisone after topical application: Comparison with simple emulsions. Int. J. Pharm. 1998;160:109–117. doi: 10.1016/S0378-5173(97)00302-5. DOI

Hagen T.A., Flynn G.L. Solubility of Hydrocortisone in Organic and Aqueous Media: Evidence for Regular Solution Behavior in Apolar Solvents. J. Pharm. Sci. 1983;72:409–414. doi: 10.1016/10.1002/jps.2600720422. PubMed DOI

Ali H.S.M., York P., Blagden N., Soltanpour S., Acree W.E., Jr., Jouyban A. Solubility of Budesonide, Hydrocortisone, and Prednisolone in Ethanol + Water Mixtures at 298.2 K. J. Chem. Eng. Data. 2010;55:578–582. doi: 10.1021/je900376r. DOI

Hua S. Comparison of in vitro dialysis release methods of loperamide-encapsulated liposomal gel for topical drug delivery. Int. J. Nanomedicine. 2014;9:735–744. doi: 10.2147/ijn.S55805. PubMed DOI PMC

Imiquimod nanocrystal-loaded dissolving microneedles prepared by DLP printing