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Nevertheless, the properties of these nanosystems still need to be improved to enable knowledge transfer to the pharmaceutical industry and the development of more efficacious topical medicines. Quality-by-design strategies, such as Box\u2013Behnken factorial design (BBD), are in line with the current need to use sustainable processes to develop new formulations. Thus, this work aimed at optimizing the physicochemical properties of transfersomes for cutaneous applications, by applying a BBD strategy to incorporate mixed edge activators with opposing hydrophilic\u2013lipophilic balance (HLB). Tween\u00ae 80 and Span\u00ae 80 were used as edge activators and ibuprofen sodium salt (IBU) was selected as the model drug. After the initial screening of the IBU solubility in aqueous media, a BBD protocol was implemented, and the optimized formulation displayed appropriate physicochemical properties for skin delivery. By comparing the optimized transfersomes to equivalent liposomes, the incorporation of mixed edge activators was found to be beneficial to upgrade the storage stability of the nanosystems. Furthermore, their cytocompatibility was shown by cell viability studies using 3D HaCaT cultures. Altogether, the data herein bode well for future advances in the use of mixed edge activators in transfersomes for the management of skin conditions.<\/jats:p>","DOI":"10.3390\/pharmaceutics15041209","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T02:02:33Z","timestamp":1681178553000},"page":"1209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mixed Edge Activators in Ibuprofen-Loaded Transfersomes: An Innovative Optimization Strategy Using Box\u2013Behnken Factorial Design"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8718-2083","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Vieira","sequence":"first","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"Department of Biomedical Sciences, University of Alcal\u00e1, Ctra. Madrid-Barcelona Km. 33.600, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}]},{"given":"J\u00e9ssica","family":"Castelo","sequence":"additional","affiliation":[{"name":"School of Health Sciences and Technologies, Universidade Lus\u00f3fona, Campo Grande 376, 1749-024 Lisboa, Portugal"}]},{"given":"Marta","family":"Martins","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"Department of Biomedical Sciences, University of Alcal\u00e1, Ctra. Madrid-Barcelona Km. 33.600, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1333-9137","authenticated-orcid":false,"given":"Nuno","family":"Saraiva","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-6213","authenticated-orcid":false,"given":"Catarina","family":"Rosado","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5407-3983","authenticated-orcid":false,"given":"Catarina","family":"Pereira-Leite","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal"},{"name":"LAQV, REQUIMTE, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0140-6736(20)31286-1","article-title":"Atopic Dermatitis","volume":"396","author":"Langan","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16082","DOI":"10.1038\/nrdp.2016.82","article-title":"Psoriasis","volume":"2","author":"Greb","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Piccione, M., Belloni Fortina, A., Ferri, G., Andolina, G., Beretta, L., Cividini, A., De Marni, E., Caroppo, F., Citernesi, U., and Di Liddo, R. (2021). Xeroderma Pigmentosum: General Aspects and Management. J. Pers. Med., 11.","DOI":"10.3390\/jpm11111146"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/j.1524-4725.2005.31608","article-title":"Long-Term Clinical Outcomes Following Treatment of Actinic Keratosis with Imiquimod 5% Cream","volume":"31","author":"Lee","year":"2006","journal-title":"Dermatol. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1021\/acs.molpharmaceut.0c00154","article-title":"Nanodelivery Systems for Topical Management of Skin Disorders","volume":"18","author":"Cui","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hmingthansanga, V., Singh, N., Banerjee, S., Manickam, S., Velayutham, R., and Natesan, S. (2022). Improved Topical Drug Delivery: Role of Permeation Enhancers and Advanced Approaches. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14122818"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113929","DOI":"10.1016\/j.addr.2021.113929","article-title":"Topical Drug Delivery: History, Percutaneous Absorption, and Product Development","volume":"177","author":"Roberts","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20780","DOI":"10.3390\/molecules191220780","article-title":"Prodrug Strategies for Enhancing the Percutaneous Absorption of Drugs","volume":"19","year":"2014","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.jconrel.2022.09.025","article-title":"Overcoming Skin Barriers through Advanced Transdermal Drug Delivery Approaches","volume":"351","author":"Phatale","year":"2022","journal-title":"J. Control Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jconrel.2016.09.008","article-title":"Transdermal Delivery from Liposomal Formulations\u2013Evolution of the Technology over the Last Three Decades","volume":"242","author":"Ashtikar","year":"2016","journal-title":"J. Control Release"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sudhakar, K., Fuloria, S., Subramaniyan, V., Sathasivam, K.V., Azad, A.K., Swain, S.S., Sekar, M., Karupiah, S., Porwal, O., and Sahoo, A. (2021). Ultraflexible Liposome Nanocargo as a Dermal and Transdermal Drug Delivery System. Nanomaterials, 11.","DOI":"10.3390\/nano11102557"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9197","DOI":"10.2147\/IJN.S237508","article-title":"The Challenge of Nanovesicles for Selective Topical Delivery for Acne Treatment: Enhancing Absorption Whilst Avoiding Toxicity","volume":"15","author":"Mancuso","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/0024-3205(80)90268-4","article-title":"Liposomes-a Selective Drug Delivery System for the Topical Route of Administration I. Lotion Dosage Form","volume":"26","author":"Mezei","year":"1980","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3109\/21691401.2014.953633","article-title":"Application of Liposomes in Medicine and Drug Delivery","volume":"44","author":"Daraee","year":"2016","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Opatha, S.A.T., Titapiwatanakun, V., and Chutoprapat, R. (2020). Transfersomes: A Promising Nanoencapsulation Technique for Transdermal Drug Delivery. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12090855"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/0005-2736(92)90154-E","article-title":"Lipid Vesicles Penetrate into Intact Skin Owing to the Transdermal Osmotic Gradients and Hydration Force","volume":"1104","author":"Cevc","year":"1992","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0168-3659(95)00056-E","article-title":"Transdermal Drug Carriers: Basic Properties, Optimization and Transfer Efficiency in the Case of Epicutaneously Applied Peptides","volume":"36","author":"Cevc","year":"1995","journal-title":"J. Control Release"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/j.xphs.2018.01.005","article-title":"Surfactant Effects on Lipid-Based Vesicles Properties","volume":"107","author":"Bnyan","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4103\/2231-4040.85524","article-title":"Transferosomes\u2014A Vesicular Transdermal Delivery System for Enhanced Drug Permeation","volume":"2","author":"Rajan","year":"2011","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ijpharm.2010.06.034","article-title":"Role of Edge Activators and Surface Charge in Developing Ultradeformable Vesicles with Enhanced Skin Delivery","volume":"397","author":"Awad","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Moqejwa, T., Marimuthu, T., Kondiah, P.P.D., and Choonara, Y.E. (2022). Development of Stable Nano-Sized Transfersomes as a Rectal Colloid for Enhanced Delivery of Cannabidiol. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040703"},{"key":"ref_22","first-page":"85","article-title":"Single versus Mixed Edge Activators in Caffeine-Loaded Transfersomes: Physicochemical and Cytotoxicity Assessment","volume":"18","author":"Guerreiro","year":"2021","journal-title":"Biomed. Biopharm. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"118817","DOI":"10.1016\/j.ijpharm.2019.118817","article-title":"Transferosomes as Nanocarriers for Drugs across the Skin: Quality by Design from Lab to Industrial Scale","volume":"573","author":"Lalatsa","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.talanta.2008.05.019","article-title":"Response Surface Methodology (RSM) as a Tool for Optimization in Analytical Chemistry","volume":"76","author":"Bezerra","year":"2008","journal-title":"Talanta"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Magalh\u00e3es, J., Chaves, L.L., Vieira, A.C., Santos, S.G., Pinheiro, M., and Reis, S. (2020). Optimization of Rifapentine-Loaded Lipid Nanoparticles Using a Quality-by-Design Strategy. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12010075"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1080\/21691401.2016.1247850","article-title":"Development and Optimization of Apigenin-Loaded Transfersomal System for Skin Cancer Delivery: In Vitro Evaluation","volume":"45","author":"Jangdey","year":"2017","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tamilarasan, N., Yasmin, B.M., Anitha, P., Umme, H., Cheng, W.H., Mohan, S., Ramkanth, S., and Janakiraman, A.K. (2022). Box\u2013Behnken Design: Optimization of Proanthocyanidin-Loaded Transferosomes as an Effective Therapeutic Approach for Osteoarthritis. Nanomaterials, 12.","DOI":"10.3390\/nano12172954"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"J\u00falio, A., Costa, J.G., Pereira-Leite, C., and Santos de Almeida, T. (2021). TransfersomILs: From Ionic Liquids to a New Class of Nanovesicular Systems. Nanomaterials, 12.","DOI":"10.3390\/nano12010007"},{"key":"ref_29","unstructured":"Vieira, J. (2021). Transfersomes as Delivery Systems of Ibuprofen for Transcutaneous Administration. [Master\u2019s Dissertation, Lus\u00f3fona University]."},{"key":"ref_30","first-page":"209","article-title":"Optimization of Gallic Acid-Loaded Transfersomes Using a Box-Behnken Factorial Design","volume":"17","author":"Ventura","year":"2020","journal-title":"Biomed. Biopharm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0009-3084(93)90053-6","article-title":"Chemical Stability of Liposomes: Implications for Their Physical Stability","volume":"64","author":"Grit","year":"1993","journal-title":"Chem. Phys. Lipids"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0378-5173(95)04281-4","article-title":"The Influence of Lipid Composition and Lamellarity of Liposomes on the Physical Stability of Liposomes upon Storage","volume":"127","author":"Duplessis","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1111\/iej.13193","article-title":"Development of an in Vitro Model to Study Tooth Cystogenesis","volume":"52","author":"Laureano","year":"2019","journal-title":"Int. Endod. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1038\/s41598-020-58569-4","article-title":"3D Tumour Spheroids for the Prediction of the Effects of Radiation and Hyperthermia Treatments","volume":"10","author":"Rivens","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0378-5173(02)00645-2","article-title":"Effect of Buffer Media Composition on the Solubility and Effective Permeability Coefficient of Ibuprofen","volume":"253","author":"Levis","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1517\/17425247.2011.605120","article-title":"Developing Oral Drug Delivery Systems Using Formulation by Design: Vital Precepts, Retrospect and Prospects","volume":"8","author":"Singh","year":"2011","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Danaei, M., Dehghankhold, M., Ataei, S., Hasanzadeh Davarani, F., Javanmard, R., Dokhani, A., Khorasani, S., and Mozafari, M. (2018). Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020057"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0378-5173(03)00183-2","article-title":"Particle Size of Liposomes Influences Dermal Delivery of Substances into Skin","volume":"258","author":"Verma","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_39","first-page":"162","article-title":"Preparation and Characterization of Ibuprofen Loaded Transferosome as a Novel Carrier for Transdermal Drug Delivery System","volume":"5","author":"Irfan","year":"2012","journal-title":"Asian J. Pharm. Clin. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/08982104.2014.950276","article-title":"Preparation of Transfersomes Encapsulating Sildenafil Aimed for Transdermal Drug Delivery: Plackett\u2013Burman Design and Characterization","volume":"25","author":"Ahmed","year":"2015","journal-title":"J. Liposome Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101985","DOI":"10.1016\/j.cis.2019.07.006","article-title":"The Why, Where, Who, How, and What of the Vesicular Delivery Systems","volume":"271","author":"Kapoor","year":"2019","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"19669","DOI":"10.1021\/ja3064342","article-title":"Structural Association of Nonsteroidal Anti-Inflammatory Drugs with Lipid Membranes","volume":"134","author":"Boggara","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3233\/JCB-179004","article-title":"In Vitro Skin Three-Dimensional Models and Their Applications","volume":"3","author":"Klicks","year":"2017","journal-title":"J. Cell Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"De Vuyst, E., Salmon, M., Evrard, C., Lambert de Rouvroit, C., and Poumay, Y. (2017). Atopic Dermatitis Studies through In Vitro Models. Front. Med., 4.","DOI":"10.3389\/fmed.2017.00119"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ijpharm.2018.09.009","article-title":"Tocopherol-Loaded Transfersomes: In Vitro Antioxidant Activity and Efficacy in Skin Regeneration","volume":"551","author":"Caddeo","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Asensio-Regalado, C., Alonso-Salces, R.M., Gallo, B., Berrueta, L.A., Era, B., Pintus, F., and Caddeo, C. (2022). Tempranillo Grape Extract in Transfersomes: A Nanoproduct with Antioxidant Activity. Nanomaterials, 12.","DOI":"10.3390\/nano12050746"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1021\/acsnano.8b03800","article-title":"Enhanced Transdermal Drug Delivery by Transfersome-Embedded Oligopeptide Hydrogel for Topical Chemotherapy of Melanoma","volume":"12","author":"Jiang","year":"2018","journal-title":"ACS NANO"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"122217","DOI":"10.1016\/j.ijpharm.2022.122217","article-title":"Trilayer Dissolving Polymeric Microneedle Array Loading Rose Bengal Transfersomes as a Novel Adjuvant in Early-Stage Cutaneous Melanoma Management","volume":"627","author":"Demartis","year":"2022","journal-title":"Int. J. Pharm."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/4\/1209\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:13:39Z","timestamp":1760123619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/4\/1209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,11]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["pharmaceutics15041209"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15041209","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,11]]}}}