{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:55:29Z","timestamp":1792511729082,"version":"4.5.0"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"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>Background: Hypertension affects 32% of adults worldwide, leading to a significant global consumption of cardiovascular medications. Atenolol, a \u03b2-adrenergic receptor blocker, is widely prescribed for cardiovascular diseases such as hypertension, angina pectoris, and myocardial infarction. According to the Biopharmaceutics Classification System (BCS), atenolol belongs to Class III, characterized by high solubility but low permeability. Currently, atenolol is commercially available in oral formulations. Increasing attention is being directed towards developing cost-effective transdermal delivery systems, due to their ease of use and better patient compliance. Eutectogels represent next-generation systems that are attracting great interest in the scientific community. Typically obtained from deep eutectic solvents (DESs) combined with gelling agents, these systems exhibit unique properties due to the intrinsic characteristics of DESs. Methods: In this study, a DES based on choline chloride as a hydrogen bond acceptor (HBA) and propylene glycol as a hydrogen bond donor (HBD) was explored to enhance the topical delivery of atenolol. The solubility of atenolol in the DES was evaluated using spectroscopic and thermodynamic measurements which confirmed the formation of hydrogen bonds between the drug and DES components. Additionally, the safety of the DES was assessed in a cell viability assay. Subsequently, we formulated eutectogels with different concentrations using animal gelatin and Tego Carbomer 140, and characterized these formulations through rheological measurements, swelling percentage, and permeation studies with Franz cells. Results: These novel eutectogels exhibit superior performance over conventional hydrogels, with a release rate of approximately 86% and 51% for Carbomer- and gelatin-based eutectogels, respectively. In contrast, comparable hydrogels released only about 27% and 35%. Conclusions: These findings underscore the promising potential of eutectogels for the transdermal delivery of atenolol.<\/jats:p>","DOI":"10.3390\/pharmaceutics16121552","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T04:47:22Z","timestamp":1733287642000},"page":"1552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Eutectogel-Based Drug Delivery: An Innovative Approach for Atenolol Administration"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6980-6799","authenticated-orcid":false,"given":"Roberta","family":"Cassano","sequence":"first","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Sole","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0584-219X","authenticated-orcid":false,"given":"Carlo","family":"Siciliano","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0064-5103","authenticated-orcid":false,"given":"Noemi","family":"Baldino","sequence":"additional","affiliation":[{"name":"Dipartimento di Ingegneria Informatica, Modellistica, Elettronica e Sistemistica, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Mileti","sequence":"additional","affiliation":[{"name":"Dipartimento di Ingegneria Informatica, Modellistica, Elettronica e Sistemistica, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8071-0288","authenticated-orcid":false,"given":"Debora","family":"Procopio","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Curcio","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Calviello","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Sezione di Patologia Generale, Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 Cattolica del Sacro Cuore, Largo F. Vito, 00168 Roma, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Serini","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Sezione di Patologia Generale, Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 Cattolica del Sacro Cuore, Largo F. Vito, 00168 Roma, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9939-4457","authenticated-orcid":false,"given":"Sonia","family":"Trombino","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5469-5459","authenticated-orcid":false,"given":"Maria Luisa","family":"Di Gioia","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Salute e Scienze della Nutrizione, Universit\u00e0 della Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/S0140-6736(21)01330-1","article-title":"Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: A pooled analysis of 1201 population-representative studies with 104 million participants","volume":"398","author":"Zhou","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S0140-6736(07)61299-9","article-title":"Essential Hypertension","volume":"370","author":"Messerli","year":"2007","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1161\/HYPERTENSIONAHA.120.15026","article-title":"International Society of Hypertension Global Hypertension Practice Guidelines","volume":"75","author":"Unger","year":"2020","journal-title":"Hypertension"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/ehjcvp\/pvy032","article-title":"ESC Council on hypertension position document on the management of hypertensive emergencies","volume":"5","author":"Lip","year":"2019","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_5","unstructured":"Antihypertensive Medications\u2014StatPearls\u2014NCBI Bookshelf (2024, March 09). National Center for Biotechnology Information, n.d, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK554579\/."},{"key":"ref_6","unstructured":"Atenolol\u2014StatPearls\u2014NCBI Bookshelf (2024, March 09). National Center for Biotechnology Information, n.d, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK539844\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0890-6238(01)00193-9","article-title":"Atenolol: Pharmacokinetic\/dynamic aspects of comparative developmental toxicity","volume":"16","author":"Tabacova","year":"2002","journal-title":"Reprod. Toxicol."},{"key":"ref_8","first-page":"367","article-title":"Oral Sustained Delivery of Atenolol from Floating Matrix Tablets\u2014Formulation and In Vitro Evaluation","volume":"31","author":"Srivastava","year":"2005","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_9","first-page":"34","article-title":"Design, formulation and evaluation of atenolol gastro retentive floating tablets","volume":"9","author":"Gunda","year":"2015","journal-title":"Asian J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5958\/2231-5713.2018.00001.6","article-title":"Formulation and Evaluation of Oro Dispersible Tablets of Atenolol by Sublimation Method","volume":"8","author":"Rangu","year":"2018","journal-title":"Asian J. Pharm. Technol."},{"key":"ref_11","first-page":"765","article-title":"Formulation and Evaluation of Floating Tablet of Atenolol for the Treatment of Hypertension","volume":"30","author":"Zaya","year":"2023","journal-title":"J. Popul. Ther. Clin. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"468","DOI":"10.2165\/00003495-199142030-00007","article-title":"Atenolol","volume":"42","author":"Wadworth","year":"1991","journal-title":"Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1208\/s12248-014-9620-9","article-title":"A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res 12, 413\u2013420, 1995\u2014Backstory of BCS","volume":"16","author":"Amidon","year":"2014","journal-title":"AAPS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.jconrel.2020.09.020","article-title":"Zero-order drug delivery: State of the art and future prospects","volume":"327","author":"Laracuente","year":"2020","journal-title":"J. Control. Release."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1007\/s10311-021-01225-8","article-title":"Basics and properties of deep eutectic solvents: A review","volume":"19","author":"Fourmentin","year":"2021","journal-title":"Environ. Chem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.gce.2021.06.001","article-title":"Deep eutectic solvents eutectogels: Progress and challenges","volume":"2","author":"Wang","year":"2021","journal-title":"Green Chem. Eng."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1039\/D1OB01814K","article-title":"Green solvents for the formation of amide linkages","volume":"20","author":"Procopio","year":"2022","journal-title":"Org. Biomol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Procopio, D., Siciliano, C., De Rose, R., Trombino, S., Cassano, R., and Di Gioia, M.L. (2022). A Br\u00f8nsted Acidic Deep Eutectic Solvent for N-Boc Deprotection. Catalysts, 12.","DOI":"10.3390\/catal12111480"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"121562","DOI":"10.1016\/j.molliq.2023.121562","article-title":"Effects of Deep Eutectic Solvents on the Activity and Stability of Enzymes","volume":"377","author":"Divsalar","year":"2023","journal-title":"J. Mol. Liq."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Di Gioia, M.L., Duarte, A.R.C., and Gawande, M.B. (2023). Editorial: Advances in the Development and Application of Deep Eutectic Solvents. Front. Chem., 11.","DOI":"10.3389\/fchem.2023.1258718"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1002\/adsc.202300725","article-title":"Visible-Light-Mediated Amide Synthesis in Deep Eutectic Solvents","volume":"366","author":"Procopio","year":"2024","journal-title":"Adv. Synth. Catal."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Procopio, D., Siciliano, C., and Di Gioia, M.L. (2024). Reactive Deep Eutectic Solvents for EDC-Mediated Amide Synthesis. Org. Biomol. Chem., 22.","DOI":"10.1039\/D3OB01673K"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Algieri, V., Maiuolo, L., Procopio, D., Costanzo, P., Nicoletta, F.P., Trombino, S., Di Gioia, M.L., and De Nino, A. (2024). Reactive Deep Eutectic Solvent for an Eco-Friendly Synthesis of Cellulose Carbamate. Polymers, 16.","DOI":"10.3390\/polym16060757"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Procopio, D., Siciliano, C., Perri, A., Guillena, G., Ram\u00f3n, D.J., and Di Gioia, M.L. (2024). Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126677"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121203","DOI":"10.1016\/j.ijpharm.2021.121203","article-title":"Deep eutectic systems: An overview of fundamental aspects, current understanding and drug delivery applications","volume":"610","author":"Chakraborty","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S0168-3659(00)00230-3","article-title":"Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery","volume":"67","author":"Woolfson","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"118015","DOI":"10.1016\/j.seppur.2020.118015","article-title":"Deep eutectic solvents in membrane science and technology: Fundamental, preparation, application, and future perspective","volume":"258","author":"Taghizadeh","year":"2021","journal-title":"Sep. Purif. Technol."},{"key":"ref_28","first-page":"e202304157","article-title":"Deep eutectic solvent and poly (vinyl alcohol) based self-healable, injectable and adhesive \u201ceutectogel\u201d: An emerging drug delivery vehicle","volume":"9","author":"Parsana","year":"2024","journal-title":"Chem. Sel."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10355","DOI":"10.1021\/acssuschemeng.8b01687","article-title":"Design of Functional Therapeutic Deep Eutectic Solvents Based on Choline Chloride and Ascorbic Acid","volume":"6","author":"Silva","year":"2018","journal-title":"ACS Sustain. Chem. Eng."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111799","DOI":"10.1016\/j.molliq.2019.111799","article-title":"Solubility and solvation behavior of some drugs in choline based deep eutectic solvents at different temperatures","volume":"297","author":"Mokhtarpour","year":"2020","journal-title":"J. Mol. Liq."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.jenvman.2019.02.062","article-title":"Removal of unleaded gasoline from water by multi-walled carbon nanotubes","volume":"237","author":"Lico","year":"2019","journal-title":"J. Environ. Manag."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1007\/s13346-021-00998-3","article-title":"Controlled release of pharmaceutical agents using eutectic modified gelatin","volume":"12","author":"Qu","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s003970000139","article-title":"A weak gel model for foods","volume":"40","author":"Gabriele","year":"2001","journal-title":"Rheol. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mileti, O., Baldino, N., Luzzi, S., Lupi, F.R., and Gabriele, D. (2024). Interfacial rheological study of \u03b2-casein\/pectin mixtures at the air\/water interface. Gels, 10.","DOI":"10.3390\/gels10010041"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.foodhyd.2013.01.020","article-title":"The influence of carrageenan on interfacial properties and short-term stability of milk whey proteins emulsions","volume":"32","author":"Seta","year":"2013","journal-title":"Food Hydrocoll."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/s00396-004-1071-x","article-title":"Spherical hydrophilic microparticles obtained by the radical copolymerisation of functionalised bovine serum albumin","volume":"283","author":"Iemma","year":"2004","journal-title":"Colloid Polym. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cassano, R., Curcio, F., Sole, R., and Trombino, S. (2023). Transdermal delivery of phloretin by gallic acid microparticles. Gels, 9.","DOI":"10.3390\/gels9030226"},{"key":"ref_38","first-page":"847","article-title":"Deep Eutectic Solvents as an Alternate to Other Harmful Solvents","volume":"12","author":"Sekhran","year":"2022","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"423","DOI":"10.34172\/PS.2020.48","article-title":"Significant Increase in the Solubility of Celecoxib in Presence of Some Deep Eutectic Solvents as Novel Sustainable Solvents and the Thermodynamic Analysis of These Systems","volume":"26","author":"Sekaari","year":"2020","journal-title":"Pharm. Sci."},{"key":"ref_40","unstructured":"European Medicines Agency (2017). Propylene Glycol Used as an Excipient, European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/report\/propylene-glycol-used-excipient-report-published-support-questions-and-answers-propylene-glycol-used-excipient-medicinal-products-human-use_en.pdf."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cherd.2020.06.012","article-title":"Deep eutectic solvent based on choline chloride and propylene glycol as a potential medium for extraction denitrificatin of hydrocarbon fuels","volume":"161","year":"2020","journal-title":"Chem. Eng. Res. Des."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"110096","DOI":"10.1016\/j.lwt.2020.110096","article-title":"Formulation of choline chloride\/ascorbic acid natural deep eutectic solvent: Characterization, solubilization capacity and antioxidant property","volume":"133","author":"Ling","year":"2020","journal-title":"LWT"},{"key":"ref_43","first-page":"98","article-title":"Enhance dissolution rate and solubility of solid drugs through pharmaceutical deep eutectic solvents","volume":"33","author":"Qader","year":"2021","journal-title":"ZJPAS Zanco J. Pure Appl. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Trombino, S., Siciliano, C., Procopio, D., Curcio, F., Lagan\u00e0, A.S., Di Gioia, M.L., and Cassano, R. (2022). Deep Eutectic Solvents for Improving the Solubilization and Delivery of Dapsone. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14020333"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.molliq.2017.06.051","article-title":"Natural deep eutectic solvents from choline chloride and betaine\u2014Physicochemical properties. Journal of Molecular Liquids","volume":"241","author":"Aroso","year":"2017","journal-title":"J. Mol. Liq."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22815","DOI":"10.1039\/C4CP02860K","article-title":"Low-melting mixtures based on choline ionic liquids","volume":"16","author":"Rengstl","year":"2014","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"383","DOI":"10.22159\/ajpcr.2019.v12i3.30727","article-title":"Formulation and stability evaluation of atenolol Gel in Two Different Bases","volume":"12","author":"Chaerunisaa","year":"2019","journal-title":"Asian J. Pharm. Clin. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.foodhyd.2013.07.007","article-title":"Rheology, Texture and Microstructure of Gelatin Gels with and without Milk Proteins","volume":"35","author":"Pang","year":"2014","journal-title":"Food Hydrocoll."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Varges, P.R., Costa, C.M., Fonseca, B.S., Naccache, M.F., and De Souza Mendes, P.R. (2019). Rheological Characterization of Carbomer\u00ae Dispersions in Water and in Water\/Glycerol Solutions. Fluids, 4.","DOI":"10.3390\/fluids4010003"},{"key":"ref_50","first-page":"30","article-title":"Extreme-environment-adapted eutectogel mediated by Heterostructure for Epidermic Sensor and Underwater Communication","volume":"655","author":"Chai","year":"2023","journal-title":"J. Colloid Interface Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/12\/1552\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:46:26Z","timestamp":1760114786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/12\/1552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,4]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["pharmaceutics16121552"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16121552","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,4]]}}}