{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T06:52:54Z","timestamp":1794034374755,"version":"4.8.0"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T00:00:00Z","timestamp":1695254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Saud University","award":["RSP2023R357"],"award-info":[{"award-number":["RSP2023R357"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>Tioconazole (TCZ) is a broad-spectrum fungicidal BCS class II drug with reported activity against Candida albicans, dermatophytes, and certain Staphylococci bacteria. We report the use of TCZ-loaded transethosomes (TEs) to overcome the skin\u2019s barrier function. TCZ-loaded TEs were fabricated by using a cold method with slight modification. Box\u2013Behnken composite design was utilized to investigate the effect of independent variables. The fabricated TEs were assessed with various physicochemical characterizations. The optimized formulation of TCZ-loaded TEs was incorporated into gel and evaluated for pH, conductivity, drug content, spreadability, rheology, in vitro permeation, ex vivo permeation, and in vitro and in vivo antifungal activity. The fabricated TCZ-loaded TEs had a % EE of 60.56 to 86.13, with particle sizes ranging from 219.1 to 757.1 nm. The SEM images showed spherically shaped vesicles. The % drug permeation was between 77.01 and 92.03. The kinetic analysis of all release profiles followed Higuchi\u2019s diffusion model. The FTIR, DSC, and XRD analysis showed no significant chemical interactions between the drug and excipients. A significantly higher antifungal activity was observed for TCZ-loaded transethosomal gel in comparison to the control. The in vivo antifungal study on albino rats indicated that TCZ-loaded transethosomal gel showed a comparable therapeutic effect in comparison to the market brand Canesten\u00ae. Molecular docking demonstrated that the TCZ in the TE composition was surrounded by hydrophobic excipients with increased overall hydrophobicity and better permeation. Therefore, TCZ in the form of transethosomal gel can serve as an effective drug delivery system, having the ability to penetrate the skin and overcome the stratum corneum barrier with improved efficacy.<\/jats:p>","DOI":"10.3390\/gels9090767","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T21:16:49Z","timestamp":1695331009000},"page":"767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Tioconazole-Loaded Transethosomal Gel Using Box\u2013Behnken Design for Topical Applications: In Vitro, In Vivo, and Molecular Docking Approaches"],"prefix":"10.3390","volume":"9","author":[{"given":"Muhammad Imran","family":"Qureshi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 66000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-2570","authenticated-orcid":false,"given":"Qazi Adnan","family":"Jamil","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 66000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8998-9454","authenticated-orcid":false,"given":"Faisal","family":"Usman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3498-4112","authenticated-orcid":false,"given":"Tanveer A.","family":"Wani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0586-3476","authenticated-orcid":false,"given":"Mudassir","family":"Farooq","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4396-5235","authenticated-orcid":false,"given":"Hamid Saeed","family":"Shah","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Syed Abdul Qadir Jillani (Out Fall) Road, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-5968","authenticated-orcid":false,"given":"Hassan","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, University of Central Punjab, 1-Khayabaan-e-Jinnah Road, Johar Town, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruqaiya","family":"Khalil","sequence":"additional","affiliation":[{"name":"Centro De Investigaciones Biom\u00e9dicas, University of Vigo (CINBO), 36310 Vigo, Spain"},{"name":"Department of Biochemistry, Genetics and Immunology, University of Vigo, 36310 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Sajjad","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-0841","authenticated-orcid":false,"given":"Seema","family":"Zargar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safina","family":"Kausar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114775","DOI":"10.1016\/j.addr.2023.114775","article-title":"Fungal infections: Immune defense, immunotherapies and vaccines","volume":"196","author":"Loh","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Senoner, T., Breitkopf, R., Treml, B., and Rajsic, S. (2023). Invasive Fungal Infections after Liver Transplantation. J. Clin. Med., 12.","DOI":"10.3390\/jcm12093238"},{"key":"ref_3","first-page":"5257","article-title":"Current status and research progress of nanoparticle application in superficial fungal infection","volume":"27","author":"Ren","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_4","first-page":"1","article-title":"Epidemiology of Invasive Candidiasis in Patients with Hematologic Malignancy on Antifungal Prophylaxis","volume":"7","author":"McCort","year":"2023","journal-title":"Mycopathologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2195001","DOI":"10.1080\/01443615.2023.2195001","article-title":"Miconazole for the treatment of vulvovaginal candidiasis. In vitro, in vivo and clinical results. Review of the literature","volume":"43","author":"Regidor","year":"2023","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"122869","DOI":"10.1016\/j.ijpharm.2023.122869","article-title":"Characterization of the hydrochloride salt hemihydrate as a new salt of the antifungal agent tioconazole","volume":"637","author":"Moroni","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_7","first-page":"61","article-title":"Nanoparticles: A Novel Antifungal Drug Delivery System","volume":"14","author":"Mali","year":"2023","journal-title":"Mater. Proc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.colsurfb.2011.12.004","article-title":"A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: Characterization and in vitro\/in vivo evaluation","volume":"92","author":"Song","year":"2012","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_9","first-page":"2024","article-title":"Ultra Deformable Nanotransethosomes: A Novel Tool to Intensify Transdermal Drug Delivery a Review","volume":"14","author":"Vijeta","year":"2023","journal-title":"J. Pharm. Negat. Results"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0168-3659(99)00222-9","article-title":"Ethosomes\u2014Novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties","volume":"65","author":"Touitou","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jconrel.2005.04.007","article-title":"Ethosomes for skin delivery of ammonium glycyrrhizinate: In vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers","volume":"106","author":"Paolino","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1208\/s12249-016-0481-7","article-title":"Glycosylated sertraline-loaded liposomes for brain targeting: QbD study of formulation variabilities and brain transport","volume":"17","author":"Harbi","year":"2016","journal-title":"AAPS PharmSciTech"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ahmed, T.A. (2020). Development of rosuvastatin flexible lipid-based nanoparticles: Promising nanocarriers for improving intestinal cells cytotoxicity. BMC Pharmacol. Toxicol., 21.","DOI":"10.1186\/s40360-020-0393-8"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.jsps.2019.02.008","article-title":"The use of chitosan-coated flexible liposomes as a remarkable carrier to enhance the antitumor efficacy of 5-fluorouracil against colorectal cancer","volume":"27","author":"Alomrani","year":"2019","journal-title":"Saudi Pharm. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ijpharm.2013.01.011","article-title":"Enhanced transdermal delivery of an anti-hypertensive agent via nanoethosomes: Statistical optimization, characterization and pharmacokinetic assessment","volume":"443","author":"Ahad","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ejpb.2012.05.011","article-title":"Tacrolimus-loaded ethosomes: Physicochemical characterization and in vivo evaluation","volume":"82","author":"Li","year":"2012","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_17","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_18","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_19","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ijpharm.2015.03.033","article-title":"Investigating the potential of employing bilosomes as a novel vesicular carrier for transdermal delivery of tenoxicam","volume":"485","author":"Abdelbary","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.ijpharm.2018.02.044","article-title":"Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation","volume":"542","author":"Mahmood","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3109\/10611860108995632","article-title":"Effect of positively and negatively charged liposomes on skin permeation of drugs","volume":"9","author":"Ogiso","year":"2001","journal-title":"J. Drug Target."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ica.2015.09.029","article-title":"Structural characterization and cytotoxic activity of tioconazole coordination compounds with cobalt (II), copper (II), zinc (II) and cadmium (II)","volume":"438","year":"2015","journal-title":"Inorganica Chim. Acta"},{"key":"ref_23","first-page":"642","article-title":"Dissolution enhancement of atovaquone through cyclodextrin complexation and phospholipid solid dispersion","volume":"5","author":"Shaji","year":"2013","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.nano.2011.10.006","article-title":"In vitro study of ethosome penetration in human skin and hypertrophic scar tissue","volume":"8","author":"Zhang","year":"2012","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1208\/s12249-010-9563-0","article-title":"Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery","volume":"12","author":"Das","year":"2011","journal-title":"AAPS PharmSciTech"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ejps.2016.03.015","article-title":"Transdermal film-loaded finasteride microplates to enhance drug skin permeation: Two-step optimization study","volume":"88","author":"Ahmed","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.msec.2015.10.035","article-title":"Spray-dried powders improve the controlled release of antifungal tioconazole-loaded polymeric nanocapsules compared to with lyophilized products","volume":"59","author":"Ribeiro","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.ijpharm.2018.07.021","article-title":"Amorphous magnesium carbonate nanoparticles with strong stabilizing capability for amorphous ibuprofen","volume":"548","author":"Yang","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.nano.2011.07.004","article-title":"Nanosized ethanolic vesicles loaded with econazole nitrate for the treatment of deep fungal infections through topical gel formulation","volume":"8","author":"Verma","year":"2012","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"171","DOI":"10.4103\/2230-973X.121284","article-title":"Cavamax W7 composite psoralen ethosomal gel versus cavamax W7 psoralen solid complex gel for topical delivery: A comparative evaluation","volume":"3","author":"Kumari","year":"2013","journal-title":"Int. J. Pharm. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1126\/science.1207032","article-title":"Imaging the microscopic structure of shear thinning and thickening colloidal suspensions","volume":"333","author":"Cheng","year":"2011","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1208\/s12249-020-01656-6","article-title":"Novel enhanced therapeutic efficacy of dapoxetine HCl by nano-vesicle transdermal gel for treatment of carrageenan-induced rat paw edema","volume":"21","author":"Salem","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jddst.2017.03.007","article-title":"Development and optimization of ketoconazole loaded nano-transfersomal gel for vaginal delivery using Box-Behnken design: In vitro, ex vivo characterization and antimicrobial evaluation","volume":"39","author":"Singh","year":"2017","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1128\/AAC.25.4.450","article-title":"Inhibition and killing of Candida albicans in vitro by five imidazoles in clinical use","volume":"25","author":"Lefler","year":"1984","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.bioorg.2017.04.002","article-title":"New 1, 2-diaryl-4-substituted-benzylidene-5-4H-imidazolone derivatives: Design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents","volume":"72","author":"Abdellatif","year":"2017","journal-title":"Bioorg. Chem."},{"key":"ref_36","first-page":"683","article-title":"Assessment of Anti-Dermatophytic Activity of Zincoderm gm Cream in Experimental Tinea Pedis in Wistar Rats","volume":"5","author":"Satyam","year":"2015","journal-title":"Int. J. Pharm. Chem. Biol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Qushawy, M., Nasr, A., Abd-Alhaseeb, M., and Swidan, S. (2018). Design, optimization and characterization of a transfersomal gel using miconazole nitrate for the treatment of candida skin infections. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10010026"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0168-3659(98)00181-3","article-title":"Liposomes as a topical delivery system: The role of size on transport studied by the EPR imaging method","volume":"59","author":"Vrhovnik","year":"1999","journal-title":"J. Control. Release"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.colsurfb.2009.03.028","article-title":"Effect of polymer viscosity on physicochemical properties and ocular tolerance of FB-loaded PLGA nanospheres","volume":"72","author":"Vega","year":"2009","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Siddiqui, A., Jain, P., Alex, T.S., Ali, M.A., Hassan, N., Haneef, J., Naseef, P.P., Kuruniyan, M.S., Mirza, M.A., and Iqbal, Z. (2022). Investigation of a Minocycline-Loaded Nanoemulgel for the Treatment of Acne Rosacea. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112322"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1080\/02713680903017500","article-title":"Sustained release and permeation of timolol from surface-modified solid lipid nanoparticles through bioengineered human cornea","volume":"34","author":"Attama","year":"2009","journal-title":"Curr. Eye Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.molliq.2016.11.114","article-title":"Development of ethosomal gel of ranolazine for improved topical delivery: In vitro and ex vivo evaluation","volume":"225","author":"Bisht","year":"2017","journal-title":"J. Mol. Liq."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ijpharm.2010.09.007","article-title":"Development, evaluation and clinical studies of Acitretin loaded nanostructured lipid carriers for topical treatment of psoriasis","volume":"401","author":"Agrawal","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.ejps.2010.09.004","article-title":"Nanoencapsulation of a water soluble drug in biocompatible polyesters. Effect of polyesters melting point and glass transition temperature on drug release behavior","volume":"41","author":"Karavelidis","year":"2010","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.sbi.2018.06.003","article-title":"Eukaryotic DNA polymerases","volume":"53","author":"Jain","year":"2018","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7394685","DOI":"10.1155\/2016\/7394685","article-title":"Development and evaluation of stability of a gel formulation containing the monoterpene borneol","volume":"2016","author":"Dantas","year":"2016","journal-title":"Sci. World J."},{"key":"ref_47","first-page":"201","article-title":"Preparation and evaluation of herbal gel formulation","volume":"1","author":"Jamadar","year":"2017","journal-title":"J. Pharm. Res. Educ."},{"key":"ref_48","first-page":"51","article-title":"Anti-aging potential of a cream containing herbal oils and honey: Formulation and in vivo evaluation of effectiveness using non-invasive biophysical techniques","volume":"10","author":"Yener","year":"2015","journal-title":"IOSR J. Pharm. Biol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.ijbiomac.2017.03.066","article-title":"Development of Curcumin loaded chitosan polymer based nanoemulsion gel: In vitro, ex vivo evaluation and in vivo wound healing studies","volume":"101","author":"Thomas","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1128\/jcm.33.5.1094-1097.1995","article-title":"Comparison of visual and spectrophotometric methods of MIC endpoint determinations by using broth microdilution methods to test five antifungal agents, including the new triazole D0870","volume":"33","author":"Pfaller","year":"1995","journal-title":"J. Clin. Microbiol."}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/9\/9\/767\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:54:39Z","timestamp":1760129679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/9\/9\/767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,21]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["gels9090767"],"URL":"https:\/\/doi.org\/10.3390\/gels9090767","relation":{},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,21]]}}}