{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:58:38Z","timestamp":1786463918715,"version":"build-2736575974"},"reference-count":107,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Al-Qabas Private College Research Award","award":["INT_2026\/04\/09SCI"],"award-info":[{"award-number":["INT_2026\/04\/09SCI"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: This study evaluates transdermal delivery of tamoxifen (TXN) as an alternative to the oral route of administration in treating breast cancer, which is the leading cause of cancer-related death in women globally. Oral TXN, a Class II drug, is associated with first-pass metabolism and serious side effects, including secondary cancers. Objectives: To enhance transdermal delivery, lipid-based transethosomes (TRS) were formulated using three different 24 factorial designs with various non-ionic surfactants, including Tween 20\u00ae, Span 20\u00ae, and Span 80\u00ae. Methods: Optimized TRS formulations were incorporated into HPMC-based gels and characterized for morphology, drug content, pH, viscosity, spreadability, ex vivo skin penetration, and deposition. Additionally, cytotoxicity and stability were assessed. Results: All TXN-TRS gels were suitable for transdermal use; however, Span 20\u00ae-based TRS gel demonstrated the highest skin penetration (40.3 \u00b1 1.5 \u00b5g\/cm2), representing a 127-fold enhancement rate compared with the non-ethosomal TXN gel. In line with the enhanced penetration profile, cellular studies on MCF-7 cells showed concentration-dependent cytotoxicity, reaching 91.24 \u00b1 1.01% inhibition at 2% w\/w after 72 h, with an IC50 value of 0.85 \u00b1 0.02% w\/w. Stability testing showed all formulations were more stable under refrigeration than at dry room temperature storage, supporting their potential as preclinical transdermal tamoxifen delivery platforms. Conclusions: Span 20\u00ae-based TXN transethosomal gel markedly enhanced skin penetration while maintaining potent cytotoxic activity, supporting its further preclinical evaluation as a promising transdermal alternative to oral tamoxifen.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080992","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:46:16Z","timestamp":1786455976000},"page":"992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design-Expert\u00ae Optimization of Tamoxifen-Loaded Transethosomal Gels: A Promising Transdermal System with Cytotoxicity and Stability Validation"],"prefix":"10.3390","volume":"18","author":[{"given":"Reem","family":"Abou Assi","sequence":"first","affiliation":[{"name":"Thoughts Formulation Lab, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Malaysia"},{"name":"EDEN Research Group, Department of Pharmacy, Al-Qabas Private College, Mosul 41002, Iraq"},{"name":"International Advisory Board, Rhein-Main Universities Alliance, 60629 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2658-9843","authenticated-orcid":false,"given":"Ahmed Bassam","family":"Farhan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Baghdad University, Baghdad 10071, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4283-7154","authenticated-orcid":false,"given":"Karam Abdullah","family":"Darweesh","sequence":"additional","affiliation":[{"name":"Discipline of Pharmaceutical Technology, College of Pharmacy, Al-Kitab University, Altun Kupri, Kirkuk 36001, Iraq"},{"name":"Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira H.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5179-5710","authenticated-orcid":false,"given":"Siok Yee","family":"Chan","sequence":"additional","affiliation":[{"name":"Thoughts Formulation Lab, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103851","DOI":"10.1016\/j.breast.2024.103851","article-title":"Inequality in breast cancer: Global statistics from 2022 to 2050","volume":"79","author":"Liao","year":"2025","journal-title":"Breast"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Miziak, P., Baran, M., B\u0142aszczak, E., Przybyszewska-Podstawka, A., Ka\u0142afut, J., Smok-Kalwat, J., Dmoszy\u0144ska-Graniczka, M., Kie\u0142bus, M., and Stepulak, A. (2023). Estrogen Receptor Signaling in Breast Cancer. Cancers, 15.","DOI":"10.3390\/cancers15194689"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.32441\/kjps.03.02.p15","article-title":"Study of the possible risk factors attributed to breast cancer in Alwasity Secondary School Kirkuk\/Iraq","volume":"3","author":"Jameel","year":"2019","journal-title":"AL-Kitab J. Pure Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4274\/ejbh.galenos.2024.2024-9-9","article-title":"A Comprehensive Review on Current Knowledge and Future Potential of Topical Therapies in Breast Cancer Treatment","volume":"21","author":"Thilagam","year":"2025","journal-title":"Eur. J. Breast Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.32441\/kjps.02.02.p14","article-title":"A comparison of mammography and ultrasonography in the evaluation of breast masses in early stage","volume":"2","author":"Mustafa","year":"2018","journal-title":"AL-Kitab J. Pure Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.survophthal.2023.07.003","article-title":"Tamoxifen retinopathy: A comprehensive review","volume":"69","author":"Tenney","year":"2024","journal-title":"Surv. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1097\/CAD.0b013e32832d6834","article-title":"Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats","volume":"20","author":"Shin","year":"2009","journal-title":"Anticancer Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Dickschen, K., Willmann, S., Thelen, K., Hempel, G., and Eissing, T. (2012). Physiologically Based Pharmacokinetic Modeling of Tamoxifen and its Metabolites in Women of Different CYP2D6 Phenotypes Provides New Insight into the Tamoxifen Mass Balance. Front. Pharmacol., 3.","DOI":"10.3389\/fphar.2012.00092"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"140010","DOI":"10.1016\/j.ijbiomac.2025.140010","article-title":"Chitosan-based hydrogels: A comprehensive review of transdermal drug delivery","volume":"298","author":"Tahir","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s11095-023-03621-x","article-title":"Fabrication and characterization of dissolving microneedles for transdermal drug delivery of apomorphine hydrochloride in Parkinson\u2019s disease","volume":"41","author":"Ando","year":"2024","journal-title":"Pharm. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"104963","DOI":"10.1016\/j.jddst.2023.104963","article-title":"A novel high-efficiency transdermal patches for combinational therapy of Alzheimer\u2019s disease: Donepezil\/vitamin B12-loaded nanofibers","volume":"89","author":"Ertas","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_12","first-page":"1727","article-title":"Effects of transdermal versus oral hormone replacement therapy in postmenopause: A systematic review","volume":"307","author":"Ferrari","year":"2023","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.4103\/JCDE.JCDE_160_23","article-title":"Comparative evaluation of efficacy of diclofenac and ketoprofen administered using transdermal drug delivery route in management of post endodontic pain: A randomized controlled clinical trial","volume":"27","author":"Karunakar","year":"2024","journal-title":"J. Conserv. Dent. Endod."},{"key":"ref_14","first-page":"2096","article-title":"Revolutionizing Cardiovascular Disease Treatment: Innovations in Transdermal Drug Delivery FOR A Heart-Healthy Future","volume":"54","author":"Jethmal","year":"2025","journal-title":"Cuest. Fisioter."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2174\/1574892816666211202154000","article-title":"Transdermal drug delivery: A step towards treatment of cancer","volume":"17","author":"Kriplani","year":"2022","journal-title":"Recent Pat. Anti-Cancer Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhao, N., Hao, J., Zhao, Y., Zhao, B., Lin, J., Song, J., Wang, M., and Luo, Z. (2025). A Novel Natural Penetration Enhancer for Transdermal Drug Delivery: In Vitro\/In Vivo Evaluation and Penetration Enhancement Mechanism. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17020254"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1615\/CritRevTherDrugCarrierSyst.2024047670","article-title":"Elevating Therapeutic Penetration: Innovations in Drug Delivery for Enhanced Permeation and Skin Cancer Management","volume":"42","author":"Chaudhary","year":"2025","journal-title":"Crit. Rev.\u2122 Ther. Drug Carr. Syst."},{"key":"ref_18","first-page":"15753","article-title":"Design, Development and Characterization of Transdermal Microneedle For Treatment of Cancer","volume":"6","author":"Kanti","year":"2025","journal-title":"Int. J. Res. Publ. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"09603271251322531","DOI":"10.1177\/09603271251322531","article-title":"Enhancing breast cancer treatment: Evaluating the efficacy of hyaluronic acid-coated tamoxifen-loaded solid lipid nanoparticles on MCF7 cells","volume":"44","author":"Ghayoumipour","year":"2025","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Abou Assi, R., Abdulbaqi, I.M., Tan, S.M., Wahab, H.A., Darwis, Y., and Chan, S.Y. (2023). Breaking barriers: Bilosomes gel potentials to pave the way for transdermal breast cancer treatment with Tamoxifen. Drug Dev. Ind. Pharm., 1\u201312.","DOI":"10.1080\/03639045.2023.2256404"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12951-016-0163-3","article-title":"Inhibition of breast cancer with transdermal tamoxifen-encapsulated lipoplex","volume":"14","author":"Lin","year":"2016","journal-title":"J. Nanobiotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"466","DOI":"10.2174\/1567201811310040011","article-title":"Tamoxifen Citrate Loaded Ethosomes for Transdermal Drug Delivery System: Preparation and Characterization","volume":"10","author":"Suresh","year":"2013","journal-title":"Curr. Drug Deliv."},{"key":"ref_23","first-page":"287","article-title":"Enhancement of transdermal delivery of tamoxifen citrate using nanoemulsion vehicle","volume":"3","author":"Pathan","year":"2011","journal-title":"Int. J. Pharm. Tech. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sundralingam, U., Chakravarthi, S., Radhakrishnan, A.K., Muniyandy, S., and Palanisamy, U.D. (2020). Efficacy of emu oil transfersomes for local transdermal delivery of 4-OH tamoxifen in the treatment of breast cancer. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12090807"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.2174\/0113816128344198250308022732","article-title":"QbD-Anchored Preparation and Assessment of Transethosomal Gel for Enhanced Skin Permeation of Tamoxifen Citrate","volume":"31","author":"Bobade","year":"2025","journal-title":"Curr. Pharm. Des."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"795","DOI":"10.2147\/DDDT.S158018","article-title":"Transethosomal gels as carriers for the transdermal delivery of colchicine: Statistical optimization, characterization, and ex vivo evaluation","volume":"12","author":"Abdulbaqi","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s13205-020-2083-z","article-title":"Herbal ethosomal gel containing luliconazole for productive relevance in the field of biomedicine","volume":"10","author":"Dave","year":"2020","journal-title":"3 Biotech"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101691","DOI":"10.1016\/j.jddst.2020.101691","article-title":"Enhanced penetration and improved therapeutic efficacy of bexarotene via topical liposomal gel in imiquimod induced psoriatic plaque model in BALB\/c mice","volume":"58","author":"Saka","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_29","first-page":"780150","article-title":"Development and Evaluation of Microemulsions for Transdermal Delivery of Insulin","volume":"2011","author":"Malakar","year":"2011","journal-title":"Int. Sch. Res. Not."},{"key":"ref_30","first-page":"3023","article-title":"Formulation, characterization, and evaluation of in vitro skin permeation and in vivo pharmacodynamics of surface-charged tripterine-loaded nanostructured lipid carriers","volume":"7","author":"Chen","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"333","DOI":"10.4103\/0975-7406.103274","article-title":"Formulation and optimization of nano-sized ethosomes for enhanced transdermal delivery of cromolyn sodium","volume":"4","author":"Rakesh","year":"2012","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1080\/08982104.2021.1955925","article-title":"Design, formulation and optimization of topical ethosomes using full factorial design: In-vitro and ex-vivo characterization","volume":"32","year":"2022","journal-title":"J. Liposome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ijpharm.2013.11.017","article-title":"Enhanced in vitro and in vivo skin deposition of apigenin delivered using ethosomes","volume":"460","author":"Shen","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5532269","DOI":"10.1155\/2021\/5532269","article-title":"The Synergistic Effects of Celastrol in combination with Tamoxifen on Apoptosis and Autophagy in MCF-7 Cells","volume":"2021","author":"Wang","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"444","DOI":"10.2174\/1567201816666190201143457","article-title":"Topical and Transdermal Drug Delivery: From Simple Potions to Smart Technologies","volume":"16","author":"Benson","year":"2019","journal-title":"Curr. Drug Deliv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/17425247.2020.1713087","article-title":"Permeation enhancers in transdermal drug delivery: Benefits and limitations","volume":"17","year":"2020","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Souto, E.B., Fernandes, A.R., Martins-Gomes, C., Coutinho, T.E., Durazzo, A., Lucarini, M., Souto, S.B., Silva, A.M., and Santini, A. (2020). Nanomaterials for skin delivery of cosmeceuticals and pharmaceuticals. Appl. Sci., 10.","DOI":"10.3390\/app10051594"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.2147\/IJN.S105016","article-title":"Ethosomal nanocarriers: The impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials","volume":"11","author":"Abdulbaqi","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"251","DOI":"10.56808\/3027-7922.2568","article-title":"Review on drug delivery applications of ethosomes: Current developments and prospects","volume":"46","author":"Shitole","year":"2022","journal-title":"Thai J. Pharm. Sci. (TJPS)"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Jovanovi\u0107, A.A., Petrovi\u0107, P., Pirkovi\u0107, A., Miti\u0107, N., Giampieri, F., Battino, M., and Dekanski, D. (2025). Ergosterol-Enriched Liposomes with Post-Processing Modifications for Serpylli Herba Polyphenol Delivery: Physicochemical, Stability and Antioxidant Assessment. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17111362"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s10953-020-01007-w","article-title":"Dynamic method for the determination of hygroscopicity of water-soluble solids","volume":"49","author":"Tereshchenko","year":"2020","journal-title":"J. Solut. Chem."},{"key":"ref_42","unstructured":"ICH (2026, May 10). ICH Harmonised Tripartite Guideline Stability Testing of New Drug Substances and Products Q1A(R2). Available online: https:\/\/database.ich.org\/sites\/default\/files\/Q1A%28R2%29%20Guideline.pdf."},{"key":"ref_43","unstructured":"ICH (2026, May 10). ICH Topic Q1C Stability Testing: Requirements for New Dosage Forms. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-q-1-c-stability-testing-requirements-new-dosage-forms-step-5_en.pdf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"145980","DOI":"10.1016\/j.foodchem.2025.145980","article-title":"Interfacial mechanisms regulating lipid digestion: A systematic study using tween surfactants with varying structural features","volume":"493","author":"Zhang","year":"2025","journal-title":"Food Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1124\/mol.105.012971","article-title":"Distinct Structural Features of Phospholipids Differentially Determine Ethanol Sensitivity and Basal Function of BK Channels","volume":"68","author":"Crowley","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1208\/s12249-019-1306-2","article-title":"Enhancement of transdermal delivery of haloperidol via spanlastic dispersions: Entrapment efficiency vs. particle size","volume":"20","author":"Fahmy","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"274","DOI":"10.4103\/0110-5558.72415","article-title":"Therapeutic and cosmeceutical potential of ethosomes: An overview","volume":"1","author":"Verma","year":"2010","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3390\/pharmaceutics3030497","article-title":"Effect of Penetration Enhancer Containing Vesicles on the Percutaneous Delivery of Quercetin through New Born Pig Skin","volume":"3","author":"Chessa","year":"2011","journal-title":"Pharmaceutics"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Yanar, F., Mosayyebi Amimeche Miet, A., Nastruzzi, C., Carugo, D., and Zhang, X. (2020). Continuous-Flow Production of Liposomes with a Millireactor under Varying Fluidic Conditions. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12111001"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"108770","DOI":"10.1016\/j.biopha.2019.108770","article-title":"Enhanced skin permeation of Methotrexate from penetration enhancer containing vesicles: In vitro optimization and in vivo evaluation","volume":"114","author":"Sadarani","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","unstructured":"N\u00e9meth, Z., Cs\u00f3ka, I., Semnani Jazani, R., Sipos, B., Haspel, H., Kozma, G., K\u00f3nya, Z., and Dob\u00f3, D.G. (2022). Quality by Design-Driven Zeta Potential Optimisation Study of Liposomes with Charge Imparting Membrane Additives. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091798"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0939-6411(97)00103-3","article-title":"The adsorption of cellulose ethers in aqueous suspensions of pyrantel pamoate: Effects on zeta potential and stability","volume":"45","author":"Duro","year":"1998","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.2147\/IJN.S400604","article-title":"Ginger extract\u2013loaded transethosomes for effective transdermal permeation and anti-inflammation in rat model","volume":"18","author":"Hassan","year":"2023","journal-title":"Int. J. Nanomed."},{"key":"ref_55","first-page":"1","article-title":"Effect of Surfactant Type, Cholesterol Content and Various Downsizing Methods on the Particle Size of Niosomes","volume":"17","author":"Nowroozi","year":"2018","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"346","DOI":"10.4103\/1735-5362.213979","article-title":"Factors affecting liposomes particle size prepared by ethanol injection method","volume":"12","author":"Shaker","year":"2017","journal-title":"Res. Pharm. Sci."},{"key":"ref_57","first-page":"261","article-title":"Effects of functional group of non-ionic surfactants on the stability of emulsion","volume":"19","author":"Ibrahim","year":"2015","journal-title":"Malays. J. Anal. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.17576\/jsm-2017-4612-22","article-title":"Size and stability of curcumin niosomes from combinations of tween 80 and span 80","volume":"46","author":"Nadzir","year":"2017","journal-title":"Sains Malays."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"112008","DOI":"10.1016\/j.jfoodeng.2024.112008","article-title":"Effects of spans on whipping capabilities of aerated emulsions: Reinforcement of fat crystal-membrane interactions","volume":"372","author":"Xie","year":"2024","journal-title":"J. Food Eng."},{"key":"ref_60","first-page":"59","article-title":"Optimisation and stability assessment of solid lipid nanoparticles using particle size and zeta potential","volume":"25","author":"Shah","year":"2014","journal-title":"J. Phys. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Vieira, J., Castelo, J., Martins, M., Saraiva, N., Rosado, C., and Pereira-Leite, C. (2023). Mixed Edge Activators in Ibuprofen-Loaded Transfersomes: An Innovative Optimization Strategy Using Box-Behnken Factorial Design. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15041209"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"23345","DOI":"10.1038\/s41598-021-02826-7","article-title":"Optimization of entrapment efficiency and release of clindamycin in microsponge based gel","volume":"11","author":"Khattab","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Giuliano, E., Paolino, D., Fresta, M., and Cosco, D. (2018). Drug-loaded biocompatible nanocarriers embedded in poloxamer 407 hydrogels as therapeutic formulations. Medicines, 6.","DOI":"10.3390\/medicines6010007"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.apsb.2017.03.002","article-title":"Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: Preparation, characterization and application in a vaginal drug delivery system","volume":"7","author":"Ci","year":"2017","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"53","DOI":"10.31436\/jop.v3i1.156","article-title":"An insight into the use and advantages of Carbopol in topical mucoadhesive drug delivery system: A systematic review","volume":"3","author":"Hamdi","year":"2023","journal-title":"J. Pharm."},{"key":"ref_66","first-page":"193","article-title":"Nanoparticles for dermal and transdermal drug delivery","volume":"4","author":"Uchechi","year":"2014","journal-title":"Appl. Nanotechnol. Drug Deliv."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Luki\u0107, M., Panteli\u0107, I., and Savi\u0107, S.D. (2021). Towards optimal ph of the skin and topical formulations: From the current state of the art to tailored products. Cosmetics, 8.","DOI":"10.3390\/cosmetics8030069"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/j.1467-2494.2006.00344.x","article-title":"Natural skin surface pH is on average below 5, which is beneficial for its resident flora","volume":"28","author":"Lambers","year":"2006","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_69","unstructured":"United States Pharmacopeia (2022). General Chapter 3 Topical and Transdermal Drug Products-Product Quality Tests, United States Pharmacopeia. USP-NF."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1208\/s12249-024-03035-x","article-title":"Transethosomes: A comprehensive review of ultra-deformable vesicular systems for enhanced transdermal drug delivery","volume":"26","author":"Seenivasan","year":"2025","journal-title":"AAPS PharmSciTech"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12944-019-1064-x","article-title":"Flurbiprofen loaded ethosomes\u2014Transdermal delivery of anti-inflammatory effect in rat model","volume":"18","author":"Paliwal","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_72","first-page":"64","article-title":"Development and characterization of ethosomes based gel formulation for enhanced topical delivery","volume":"3","author":"Sachan","year":"2017","journal-title":"MIT Int. J. Pharm. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.crfs.2021.06.003","article-title":"Physics of agarose fluid gels: Rheological properties and microstructure","volume":"4","author":"Ghebremedhin","year":"2021","journal-title":"Curr. Res. Food Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"30","DOI":"10.9734\/jpri\/2021\/v33i24B31439","article-title":"Formulation and Optimization of Zaltoprofen Loaded Ethosomal Gel by using 23 Full Factorial Designs","volume":"33","author":"Anju","year":"2021","journal-title":"J. Pharm. Res. Int."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"789","DOI":"10.25258\/ijddt.12.2.57","article-title":"Perspective Impact of Gelling Agents on the Mechanistic Behavior for the Topical Delivery of Flufenamic Acid Nano-Ethosomal Dispersion","volume":"12","author":"Muslim","year":"2022","journal-title":"Int. J. Drug Deliv. Technol."},{"key":"ref_76","first-page":"103","article-title":"Formulation and evaluation of transdermal gel of sildenafil citrate","volume":"1","author":"Patel","year":"2012","journal-title":"Int. J. Pharm. Res. Allied Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"104595","DOI":"10.1016\/j.amsu.2022.104595","article-title":"Ethosomes: A novel drug carrier","volume":"82","author":"Chauhan","year":"2022","journal-title":"Ann. Med. Surg."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Shinde, P., Page, A., and Bhattacharya, S. (2023). Ethosomes and their monotonous effects on skin cancer disruption. Front. Nanotechnol., 5.","DOI":"10.3389\/fnano.2023.1087413"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e08938","DOI":"10.1016\/j.heliyon.2022.e08938","article-title":"Physicochemical and biopharmaceutical aspects influencing skin permeation and role of SLN and NLC for skin drug delivery","volume":"8","author":"Souto","year":"2022","journal-title":"Heliyon"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Alam, S., Algahtani, M.S., Ahmad, M.Z., and Ahmad, J. (2020). Investigation utilizing the HLB concept for the development of moisturizing cream and lotion: In-vitro characterization and stability evaluation. Cosmetics, 7.","DOI":"10.3390\/cosmetics7020043"},{"key":"ref_81","first-page":"6847971","article-title":"Niosome: A promising nanocarrier for natural drug delivery through blood-brain barrier","volume":"2018","author":"Gharbavi","year":"2018","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.ijbiomac.2019.11.146","article-title":"Oxidized konjac glucomannan-cassava starch and sucrose esters as novel excipients for sustained-release matrix tablets","volume":"156","author":"Liu","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0378-5173(00)00427-0","article-title":"Comparative enhancer effects of Span\u00ae 20 with Tween\u00ae 20 and Azone\u00ae on the in vitro percutaneous penetration of compounds with different lipophilicities","volume":"202","author":"Llinares","year":"2000","journal-title":"Int. J. Pharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1211\/jpp.58.2.0002","article-title":"Skin permeation of retinol in Tween 20-based deformable liposomes: In-vitro evaluation in human skin and keratinocyte models","volume":"58","author":"Oh","year":"2006","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Akhtar, N., Rehman, M., Khan, H., Rasool, F., Saeed, T., and Murtaz, G. (2011). Penetration enhancing effect of polysorbate 20 and 80 on the in vitro percutaneous absorption of lascorbic acid. Trop. J. Pharm. Res., 10.","DOI":"10.4314\/tjpr.v10i3.1"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1021\/acs.jpcb.2c07209","article-title":"Plant terpenoid permeability through biological membranes explored via molecular simulations","volume":"127","author":"Raza","year":"2023","journal-title":"J. Phys. Chem. B"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4103\/0975-7406.92724","article-title":"Status of surfactants as penetration enhancers in transdermal drug delivery","volume":"4","author":"Som","year":"2012","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"14451","DOI":"10.3390\/molecules200814451","article-title":"Absorption-enhancing effects of bile salts","volume":"20","author":"Moghimipour","year":"2015","journal-title":"Molecules"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Pavlovi\u0107, N., Golo\u010dorbin-Kon, S., \u00d0ani\u0107, M., Stanimirov, B., Al-Salami, H., Stankov, K., and Mikov, M. (2018). Bile acids and their derivatives as potential modifiers of drug release and pharmacokinetic profiles. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01283"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.cherd.2008.06.002","article-title":"Transdermal drug delivery by coated microneedles: Geometry effects on effective skin thickness and drug permeability","volume":"86","author":"Davidson","year":"2008","journal-title":"Chem. Eng. Res. Des."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s43094-022-00418-4","article-title":"Ex vivo permeation parameters and skin deposition of melatonin-loaded microemulsion for treatment of alopecia","volume":"8","author":"Elshall","year":"2022","journal-title":"Future J. Pharm. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1080\/01932691.2024.2399122","article-title":"Enhancing topical acitretin delivery: Formulation and evaluation of solid lipid nanoparticles for efficient skin therapy through in vitro and ex vivo testing","volume":"47","author":"Panmand","year":"2024","journal-title":"J. Dispers. Sci. Technol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1208\/s12249-025-03074-y","article-title":"Co-Delivery of Tacrolimus and Thymoquinone Topically by Nanostructured Lipid Carrier Gel for Enhanced Efficacy Against Psoriasis","volume":"26","author":"Alam","year":"2025","journal-title":"AAPS PharmSciTech"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s43042-020-00120-1","article-title":"Effect of Ag nanoparticles on viability of MCF-7 and Vero cell lines and gene expression of apoptotic genes","volume":"22","author":"Sangour","year":"2021","journal-title":"Egypt. J. Med. Hum. Genet."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Cascione, M., De Matteis, V., Mandriota, G., Leporatti, S., and Rinaldi, R. (2019). Acute cytotoxic effects on morphology and mechanical behavior in MCF-7 induced by TiO2NPs exposure. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143594"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"095413","DOI":"10.1088\/2053-1591\/ab33af","article-title":"Graphene nanoparticles induces apoptosis in MCF-7 cells through mitochondrial damage and NF-KB pathway","volume":"6","author":"Alsaedi","year":"2019","journal-title":"Mater. Res. Express"},{"key":"ref_97","first-page":"528784","article-title":"Membrane Fusion Induced by Small Molecules and Ions","volume":"2011","author":"Sarkar","year":"2011","journal-title":"J. Lipids"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Danaei, M., Dehghankhold, M., Ataei, S., Hasanzadeh Davarani, F., Javanmard, R., Dokhani, A., Khorasani, S., and Mozafari, M.R. (2018). Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020057"},{"key":"ref_99","unstructured":"Akinosho, H.O. (2012). The Role of Structure-Function Relationships in Hydroxypropyl Methylcellulose on Emulsion Stability. [Master\u2019s Thesis, University of Georgia]."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"112969","DOI":"10.1016\/j.lwt.2021.112969","article-title":"Determination of the pH-and thermal stability mechanism of lipophilic protein\u2013hydroxypropyl methylcellulose oil-in-water emulsion","volume":"155","author":"Zhong","year":"2022","journal-title":"LWT"},{"key":"ref_101","unstructured":"AntonPaar (2026, May 23). The Principles of Dynamic Light Scattering. Available online: https:\/\/wiki.anton-paar.com\/us-en\/the-principles-of-dynamic-light-scattering\/."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1007\/s00396-014-3276-y","article-title":"Application of the zeta potential measurements to explanation of colloidal Cr2O3 stability mechanism in the presence of the ionic polyamino acids","volume":"292","author":"Ostolska","year":"2014","journal-title":"Colloid Polym. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"730","DOI":"10.3109\/10837450.2012.727001","article-title":"Effect of fixed aqueous layer thickness of polymeric stabilizers on zeta potential and stability of aripiprazole nanosuspensions","volume":"18","author":"Abdelbary","year":"2013","journal-title":"Pharm. Dev. Technol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"20","DOI":"10.4103\/japtr.JAPTR_332_18","article-title":"Proniosomal gel-mediated topical delivery of fluconazole: Development: In vitro: Characterization, and microbiological evaluation","volume":"10","author":"Khalifa","year":"2019","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1248\/cpb.58.1195","article-title":"Preparation of gel-core-solid lipid nanoparticle: A novel way to improve the encapsulation of protein and peptide","volume":"58","author":"Yang","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"38","DOI":"10.2174\/1876402911666190603093550","article-title":"Formulation and characterization of transethosomes for enhanced transdermal delivery of propranolol hydrochloride","volume":"12","author":"Kumar","year":"2020","journal-title":"Micro Nanosyst."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"109","DOI":"10.22270\/jddt.v12i1.5190","article-title":"Preparation and Characterization of Ethosomes for Topical Delivery of Clindamycin","volume":"12","author":"Powale","year":"2022","journal-title":"J. Drug Deliv. Ther."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:47:58Z","timestamp":1786456078000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":107,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18080992"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18080992","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}