{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T01:56:32Z","timestamp":1788054992055,"version":"build-2784847793"},"reference-count":32,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT &amp; Future Planning","award":["NRF-2019R1C1C1004211"],"award-info":[{"award-number":["NRF-2019R1C1C1004211"]}]},{"name":"This research has been done by the author(s) working at the Department of Pharmacy of Dankook University. Department of Pharmacy was supported by the Research-Focused Department Promotion Project as a part of the University Innovation Support Program 2020","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The incorporation of permeation enhancers in topical preparations has been recognized as a simple and valuable approach to improve the penetration of antifungal agents into toenails. In this study, to improve the toenail delivery of efinaconazole (EFN), a triazole derivative for onychomycosis treatment, topical solutions containing different penetration enhancers were designed, and the permeation profiles were evaluated using bovine hoof models. In an in vitro permeation study in a Franz diffusion cell, hydroalcoholic solutions (HSs) containing lipophilic enhancers, particularly prepared with propylene glycol dicaprylocaprate (Labrafac PG), had 41% higher penetration than the HS base. Moreover, the combination of hydroxypropyl-\u03b2-cyclodextrin with Labrafac PG further facilitated the penetration of EFN across the hoof membrane. In addition, this novel topical solution prepared with both lipophilic and hydrophilic enhancers was physicochemically stable, with no drug degradation under ambient conditions (25 \u00b0C, for 10 months). Therefore, this HS system can be a promising tool for enhancing the toenail permeability and therapeutic efficacy of EFN.<\/jats:p>","DOI":"10.3390\/molecules26061650","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T12:01:02Z","timestamp":1615896062000},"page":"1650","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effect of Penetration Enhancers on Toenail Delivery of Efinaconazole from Hydroalcoholic Preparations"],"prefix":"10.3390","volume":"26","author":[{"given":"Jun Soo","family":"Park","sequence":"first","affiliation":[{"name":"Colledge of Pharmacy, Dankook University, Dongnam-gu, Cheonan 330-714, Chungnam, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin 446-905, Gyeonggi, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung Jin","family":"Ho","sequence":"additional","affiliation":[{"name":"Colledge of Pharmacy, Dankook University, Dongnam-gu, Cheonan 330-714, Chungnam, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Woo","family":"Park","sequence":"additional","affiliation":[{"name":"Colledge of Pharmacy, Dankook University, Dongnam-gu, Cheonan 330-714, Chungnam, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun A.","family":"Kim","sequence":"additional","affiliation":[{"name":"Colledge of Pharmacy, Dankook University, Dongnam-gu, Cheonan 330-714, Chungnam, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Seok","family":"Choi","sequence":"additional","affiliation":[{"name":"Colledge of Pharmacy, Dankook University, Dongnam-gu, Cheonan 330-714, Chungnam, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Woo","family":"Jang","sequence":"additional","affiliation":[{"name":"Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin 446-905, Gyeonggi, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung Joo","family":"Kang","sequence":"additional","affiliation":[{"name":"Colledge of Pharmacy, Dankook University, Dongnam-gu, Cheonan 330-714, Chungnam, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.mpmed.2009.02.014","article-title":"Nails and hair","volume":"37","year":"2009","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1468-3083.2004.00851.x","article-title":"Risk factors associated with onychomycosis","volume":"18","author":"Sigurgeirsson","year":"2004","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1128\/AAC.02056-12","article-title":"Comparison of In Vitro ntifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis","volume":"57","author":"Siu","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1128\/AAC.02063-12","article-title":"Mechanism of action of efinaconazole, a novel triazole antifungal agent","volume":"57","author":"Tatsumi","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.1128\/AAC.00111-14","article-title":"The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment","volume":"58","author":"Sugiura","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","unstructured":"(2020, October 21). FDA Label of JUBLIA\u00ae (efinaconazole) Topical Solution, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/203567s000lbl.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ijpharm.2012.04.024","article-title":"The human nail\u2014Barrier characterisation and permeation enhancement","volume":"435","author":"Walters","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"239","DOI":"10.4155\/tde-2016-0090","article-title":"High failure rate of transungal drug delivery: Need for new strategies","volume":"8","author":"Tiwary","year":"2017","journal-title":"Ther. Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cutr\u00edn-G\u00f3mez, E., Anguiano-Igea, S., Delgado-Charro, M.B., G\u00f3mez-Amoza, J.L., and Otero-Espinar, F.J. (2018). Effect of penetration enhancers on drug nail permeability from Cyclodextrin\/Poloxamer-soluble polypseudorotaxane-based nail lacquers. Pharm., 10.","DOI":"10.3390\/pharmaceutics10040273"},{"key":"ref_10","first-page":"521","article-title":"Anatomy of the nail","volume":"6","author":"Dykyj","year":"1989","journal-title":"Clin. Poditr. Med. Sur."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1208\/s12249-019-1591-9","article-title":"Mechanistic insights of formulation approaches for the treatment of nail infection: Conventional and novel drug delivery approaches","volume":"21","author":"Vikas","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1002\/jps.24459","article-title":"Efinaconazole topical solution, 10%: Formulation development program of a new topical treatment of toenail onychomycosis","volume":"104","author":"Bhatt","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1080\/10717544.2019.1687612","article-title":"Preparation and in vivo evaluation of a highly skin- and nail-permeable efinaconazole topical formulation for enhanced treatment of onychomycosis","volume":"26","author":"Lee","year":"2019","journal-title":"Drug Deliv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ijpharm.2008.11.009","article-title":"Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement","volume":"370","author":"Brown","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jconrel.2009.08.016","article-title":"In vivo transungual iontophoresis: Effect of DC current application on ionic transport and on transonychial water loss","volume":"140","author":"Dutet","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"769","DOI":"10.3109\/1061186X.2014.929138","article-title":"Insights into drug delivery across the nail plate barrier","volume":"22","author":"Saner","year":"2014","journal-title":"J. Drug Target."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.colsurfb.2006.05.008","article-title":"Keratin\u2013rhamnolipids and keratin\u2013sodium dodecyl sulfate interactions at the air\/water interface","volume":"52","author":"Sezgin","year":"2006","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1211\/jpp.61.04.0003","article-title":"A study on the effect of inorganic salts in transungual drug delivery of terbinafine","volume":"61","author":"Nair","year":"2009","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hui, X., Wester, R.C., and Maibach, H.I. (2010). Nail penetration. Textbook of Cosmetic Dermatology, Informa UK Limited.","DOI":"10.3109\/9781841847641.007"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/950358","article-title":"Hydroxypropyl-\u03b2-cyclodextrin: A Novel Transungual Permeation Enhancer for Development of Topical Drug Delivery System for Onychomycosis","volume":"2014","author":"Chouhan","year":"2014","journal-title":"J. Drug Deliv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.ejps.2017.03.043","article-title":"Topical delivery of anthramycin I. Influence of neat solvents","volume":"104","author":"Haque","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.15171\/apb.2016.03","article-title":"The effect of various vehicles on the naproxen permeability through rat skin: A mechanistic study by DSC and FT-IR Techniques","volume":"6","author":"Salimi","year":"2016","journal-title":"Adv. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cutr\u00edn-G\u00f3mez, E., Anguiano-Igea, S., Delgado-Charro, M.B., G\u00f3mez-Amoza, J.L., and Otero-Espinar, F.J. (2018). Effect on nail structure and transungual permeability of the ethanol and poloxamer ratio from cyclodextrin-soluble polypseudorotaxanes based nail lacquer. Pharm., 10.","DOI":"10.3390\/pharmaceutics10030156"},{"key":"ref_24","first-page":"461","article-title":"Chemical and physical strategies in onychomycosis topical treatment: A review","volume":"55","author":"Angelo","year":"2016","journal-title":"Med. Mycol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1365-2133.1980.tb07257.x","article-title":"An assessment of factors influencing flexibility of human fingernails","volume":"103","author":"Finlay","year":"1980","journal-title":"Br. J. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9252","DOI":"10.3390\/molecules15129252","article-title":"Antioxidant and anti-inflammatory activities of essential oils: A short review","volume":"15","author":"Miguel","year":"2010","journal-title":"Molecules"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000503305","article-title":"An open study to evaluate effectiveness and tolerability of a nail oil composed of vitamin E and essential oils in mild to moderate distal subungual onychomycosis","volume":"6","author":"Alessandrini","year":"2019","journal-title":"Ski. Appendage Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s11046-013-9622-7","article-title":"Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of trichophyton rubrum","volume":"175","author":"Flores","year":"2013","journal-title":"Mycopathology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"838","DOI":"10.3109\/03639045.2013.788016","article-title":"Ciclopirox delivery into the human nail plate using novel lipid diffusion enhancers","volume":"40","author":"Hafeez","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104753","DOI":"10.1016\/j.microc.2020.104753","article-title":"RP-HPLC method for quantitative estimation of Efinaconazole in topical microemulsion and microemulsion-based-gel formulations and in presence of its degradation products","volume":"155","author":"Vikas","year":"2020","journal-title":"Microchem. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jconrel.2011.08.021","article-title":"Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: Implications for drug delivery","volume":"156","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1161\/01.CIR.6.6.862","article-title":"Skin temperature response of normal human subjects to various conditions","volume":"6","author":"Walter","year":"1952","journal-title":"Circulation"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1650\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:36:25Z","timestamp":1760160985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,16]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["molecules26061650"],"URL":"https:\/\/doi.org\/10.3390\/molecules26061650","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,16]]}}}