{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:02:31Z","timestamp":1792623751352,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Bisoprolol hemifumarate (BH) is an antihypertensive drug that is used as first-line treatment for chronic hypertension and angina pectoris. Our study was performed to enhance the transdermal delivery of BH, a hydrophilic drug active with high molecular weight, through differently prepared hydrogels. The synergistic effect of permeation enhancers and iontophoresis was investigated via both ex vivo and in vivo permeation studies. Ex vivo iontophoretic permeation studies were performed by using male albino Wistar rat skin. Cellosolve\u00ae hydrogel (F7) showed a 1.5-fold increase in Q180, Jss, and FER compared to F5 (lacking permeation enhancer). BH pharmacokinetic data were studied in human volunteers, following transdermal delivery of F7, using Phoresor\u00ae Unit II iontophoresis device, compared to conventional oral tablets. F7 showed 1.9- and 2-fold higher values of Cmax and AUC0\u201340, respectively compared to Concor\u00ae tablets, as well as a smaller Tmax (2.00 \u00b1 2.00 h). The relative bioavailability of F7 was found to be 201.44%, relative to Concor\u00ae tablets, demonstrating the significantly enhanced transdermal permeation of BH from the selected hydrogel by iontophoresis, in human volunteers. Finally, results showed the successful utility of permeation enhancers combined with iontophoresis in significantly enhanced transdermal permeation of BH, despite its large molecular weight and hydrophilic nature. Therefore, this strategy could be employed as a successful alternative route of administration to conventional oral tablets.<\/jats:p>","DOI":"10.3390\/pharmaceutics13050682","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T05:30:08Z","timestamp":1620624608000},"page":"682","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Enhanced Transdermal Delivery of Bisoprolol Hemifumarate via Combined Effect of Iontophoresis and Chemical Enhancers: Ex Vivo Permeation\/In Vivo Pharmacokinetic Studies"],"prefix":"10.3390","volume":"13","author":[{"given":"Mahmoud H.","family":"Teaima","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Azmi Ahmed","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Obour Pharmaceutical Industries, Cairo 13024, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randa Tag","family":"Abd El Rehem","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saadia A.","family":"Tayel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"El-Nabarawi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahinaze A.","family":"Fouad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Ahram Canadian University, Giza 19228, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.4330\/wjc.v4.i5.135","article-title":"Hypertension in the elderly","volume":"4","author":"Lionakis","year":"2012","journal-title":"World J. Cardiol."},{"key":"ref_2","first-page":"136","article-title":"Hypertension in the elderly","volume":"12","author":"Nicolas","year":"2014","journal-title":"Cardiovasc. Hematol. Agents Med. Chem. Former. Curr. Med. Chem. Cardiovasc. Hematol. Agents"},{"key":"ref_3","first-page":"730624","article-title":"Use of response surface methodology in the formulation and optimization of bisoprolol fumarate matrix tablets for sustained drug release","volume":"2012","author":"Malakar","year":"2012","journal-title":"Int. Sch. Res. Not."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4103\/0975-7406.116803","article-title":"Development and evaluation of fixed dose bi therapy sublingual tablets for treatment stress hypertension and anxiety","volume":"5","author":"Tayel","year":"2013","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_5","unstructured":"Tayel, S.A., Foda, N., and Louis, D. (2018). Bisoprolol Hemifumarate Matrix Tablets for Sustained Release: Preparation and Evaluation, Inventi Journals Pvt.Ltd."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5575","DOI":"10.5958\/0974-360X.2019.00966.1","article-title":"Orodispersible Tablets: Novel Strategies and future challenges in Drug Delivery","volume":"12","author":"Malaak","year":"2019","journal-title":"Res. J. Pharm. Technol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1007\/s11095-009-9956-5","article-title":"Utility of nanosized microemulsion for transdermal delivery of tolterodine tartrate: Ex-vivo permeation and in-vivo pharmacokinetic studies","volume":"26","author":"Elshafeey","year":"2009","journal-title":"Pharm. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Rastogi, V., and Yadav, P. (2014). Transdermal drug delivery system: An overview. AJP Free Full Text Artic. Asian J. Pharm., 6.","DOI":"10.4103\/0973-8398.104828"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1002\/jps.20140","article-title":"Effect of lipid bilayer alteration on transdermal delivery of a high-molecular-weight and lipophilic drug: Studies with paclitaxel","volume":"93","author":"Panchagnula","year":"2004","journal-title":"J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1023\/A:1015314314796","article-title":"Transdermal delivery of highly lipophilic drugs: In vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations","volume":"19","author":"Funke","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_11","first-page":"484","article-title":"Development of Sublingual tablets of Bisoprolol Hemifumarate\/Hydroxypropyl-[beta]-Cyclodextrin Complex for Potential treatment of Angina Pectoris","volume":"4","author":"Kharshoum","year":"2012","journal-title":"Int. J. Drug Deliv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/BF03190266","article-title":"Recent developments in topical and transdermal delivery","volume":"21","author":"Hadgraft","year":"1996","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1023\/A:1015374600683","article-title":"Transdermal iontophoresis of tacrine in vivo","volume":"19","author":"Kankkunen","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3797\/scipharm.1108-20","article-title":"Iontophoresis: A potential emergence of a transdermal drug delivery system","volume":"80","author":"Dhote","year":"2012","journal-title":"Sci. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ejpb.2010.03.011","article-title":"Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: Effect of experimental parameters and skin type on drug stability and transport kinetics","volume":"75","author":"Merino","year":"2010","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ejps.2017.03.009","article-title":"Peptide dendrimer-conjugates of ketoprofen: Synthesis and ex vivo and in vivo evaluations of passive diffusion, sonophoresis and iontophoresis for skin delivery","volume":"102","author":"Hegde","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/09546634.2019.1589640","article-title":"Iontophoretic delivery of lidocaine hydrochloride through ex-vivo human skin","volume":"31","author":"Manjunatha","year":"2019","journal-title":"J. Dermatol. Treat."},{"key":"ref_18","first-page":"301","article-title":"Formulation and release of alaptide from cellulose-based hydrogels","volume":"81","year":"2013","journal-title":"Acta Vet. Brno"},{"key":"ref_19","first-page":"283","article-title":"Proniosomes as nano-carrier for transdermal delivery of atenolol niosomal gel","volume":"7","year":"2017","journal-title":"Int. J. Drug Deliv. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.ijpharm.2013.06.009","article-title":"Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro\/in vivo evaluation","volume":"453","author":"Fouad","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0378-5173(03)00249-7","article-title":"Investigation into the potential of iontophoresis facilitated delivery of ketorolac","volume":"260","author":"Tiwari","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_22","first-page":"663","article-title":"Electrically assisted transdermal delivery of escin","volume":"4","author":"Teaima","year":"2012","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ijpharm.2016.04.006","article-title":"Novel instantly-soluble transmucosal matrix (ISTM) using dual mechanism solubilizer for sublingual and nasal delivery of dapoxetine hydrochloride: In-vitro\/in-vivo evaluation","volume":"505","author":"Fouad","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_24","first-page":"503","article-title":"Enhanced transdermal delivery of granisetron by using iontophoresis","volume":"11","author":"Panzade","year":"2012","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3386","DOI":"10.1021\/acsbiomaterials.7b00706","article-title":"Self-assembling peptide nanofiber hydrogels for controlled ocular delivery of timolol maleate","volume":"3","author":"Karavasili","year":"2017","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.jpba.2007.03.001","article-title":"LC\u2013ESI-MS method for the determination of bisoprolol in human plasma","volume":"44","author":"Ding","year":"2007","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3109\/10837450.2012.659258","article-title":"Rapidly absorbed orodispersible tablet containing molecularly dispersed felodipine for management of hypertensive crisis: Development, optimization and in vitro\/in vivo studies","volume":"18","author":"Basalious","year":"2013","journal-title":"Pharm. Dev. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S1043-6618(03)00016-1","article-title":"Effect of iontophoresis and fatty acids on permeation of arginine vasopressin through rat skin","volume":"47","author":"Nair","year":"2003","journal-title":"Pharmacol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0168-3659(96)01452-6","article-title":"Modifications induced on stratum corneum structure after in vitro iontophoresis: ATR-FTIR and X-ray scattering studies","volume":"42","author":"Jadoul","year":"1996","journal-title":"J. Control. Release"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1208\/ps050214","article-title":"Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin","volume":"5","author":"Meidan","year":"2003","journal-title":"AAPS Pharmsci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100462","DOI":"10.1016\/j.fpsl.2020.100462","article-title":"Fabrication of antimicrobial films based on hydroxyethylcellulose and ZnO for food packaging application","volume":"23","author":"Hong","year":"2020","journal-title":"Food Packag. Shelf Life"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0378-5173(99)00345-2","article-title":"Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate","volume":"193","author":"Raghavan","year":"2000","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2174\/156720107779314767","article-title":"Development of nitrendipine transdermal patches: In vitro and ex vivo characterization","volume":"4","author":"Gannu","year":"2007","journal-title":"Curr. Drug Deliv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26S","DOI":"10.1177\/1091581820951557","article-title":"Safety assessment of pegylated alkyl glycerides as used in cosmetics","volume":"39","author":"Fiume","year":"2020","journal-title":"Int. J. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0168-3659(00)00325-4","article-title":"NMR characterisation and transdermal drug delivery potential of microemulsion systems","volume":"69","author":"Kreilgaard","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_36","first-page":"256","article-title":"In vitro permeation of carvedilol through porcine skin: Effect of vehicles and penetration enhancers","volume":"62","author":"Gannu","year":"2008","journal-title":"PDA J. Pharm. Sci. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/jphp.12206","article-title":"Effect of combination of hydrophilic and lipophilic permeation enhancers on the skin permeation of kahalalide F","volume":"66","author":"Shah","year":"2014","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4172\/2329-9053.1000113","article-title":"Role of surfactants as penetration enhancer in transdermal drug delivery system","volume":"2","author":"Pandey","year":"2014","journal-title":"J. Mol. Pharm. Org. Process. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1046\/j.1467-2494.1999.203164.x","article-title":"Derivatization Procedure and HPLC Determination of 2-Ethoxyethanol in Cosmetic Samples","volume":"21","author":"Mariani","year":"1999","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_40","unstructured":"Copestake, P., and World Health Organization (2010). Selected 2-Alkoxyethanols, World Health Organization."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0928-0987(99)00075-5","article-title":"Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations","volume":"9","author":"Mura","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ejpb.2010.12.010","article-title":"Ex vivo skin delivery of diclofenac by transcutol containing liposomes and suggested mechanism of vesicle\u2013skin interaction","volume":"78","author":"Manconi","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ijpharm.2014.12.055","article-title":"Transdermal baicalin delivery using diethylene glycol monoethyl ether-mediated cubic phase gel","volume":"479","author":"Zhang","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.1208\/s12249-018-1196-8","article-title":"Skin penetration and permeation properties of Transcutol\u00ae\u2014neat or diluted mixtures","volume":"19","author":"Osborne","year":"2018","journal-title":"Aaps Pharmscitech"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/5\/682\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:58:38Z","timestamp":1760162318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/5\/682"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,10]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["pharmaceutics13050682"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13050682","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,10]]}}}