{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:42:11Z","timestamp":1791477731056,"version":"4.3.4"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science","award":["18K06769"],"award-info":[{"award-number":["18K06769"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study designed the transdermal formulations containing indomethacin (IMC)\u20141% IMC was crushed with 0.5% methylcellulose and 5% 2-hydroxypropyl-\u03b2-cyclodextrin by the bead mill method, and the milled IMC was gelled with or without 2% l-menthol (a permeation enhancer) by Carbopol\u00ae 934 (without menthol, N-IMC gel; with menthol, N-IMC\/MT gel). In addition, the drug release, skin penetration and percutaneous absorption of the N-IMC\/MT gel were investigated. The particle sizes of N-IMC gel were approximately 50\u2013200 nm, and the combination with l-menthol did not affect the particle characterization of the transdermal formulations. In an in vitro experiment using a Franz diffusion cell, the skin penetration in N-IMC\/MT gel was enhanced than the N-IMC gel, and the percutaneous absorption (AUC) from the N-IMC\/MT gel was 2-fold higher than the N-IMC gel. On the other hand, the skin penetration from the N-IMC\/MT gel was remarkably attenuated at a 4 \u00b0C condition, a temperature that inhibits all energy-dependent endocytosis. In conclusion, this study designed transdermal formulations containing IMC solid nanoparticles and l-menthol, and found that the combination with l-menthol enhanced the skin penetration of the IMC solid nanoparticles. In addition, the energy-dependency of the skin penetration of IMC solid nanoparticles was demonstrated. These findings suggest the utility of a transdermal drug delivery system to provide the easy application of solid nanoparticles (SNPs).<\/jats:p>","DOI":"10.3390\/ijms20153644","type":"journal-article","created":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T08:45:39Z","timestamp":1564130739000},"page":"3644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles"],"prefix":"10.3390","volume":"20","author":[{"given":"Noriaki","family":"Nagai","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Ogata","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Fukuoka","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Otake","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Nakazawa","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohito","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.bpg.2009.11.005","article-title":"Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract","volume":"24","author":"Sostres","year":"2010","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.mpmed.2011.12.027","article-title":"Non-steroidal anti-inflammatory drugs","volume":"40","author":"Bateman","year":"2012","journal-title":"Medicine (Baltimore)"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.survophthal.2009.07.005","article-title":"Nonsteroidal anti-inflammatory drugs in ophthalmology","volume":"5","author":"Kim","year":"2010","journal-title":"Surv. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.tox.2008.10.005","article-title":"Involvement of interleukin 18 in indomethacin-induced lesions of the gastric mucosa in adjuvant-induced arthritis rat","volume":"255","author":"Nagai","year":"2009","journal-title":"Toxicology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1254\/jjp.89.1","article-title":"Alteration of gastric ulcerogenic and healing responses in rats with adjuvant-induced arthritis","volume":"89","author":"Kato","year":"2002","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijpharm.2008.12.004","article-title":"Design and in vivo evaluation of an indapamide transdermal patch","volume":"370","author":"Ren","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jconrel.2008.07.012","article-title":"Intra-articular penetration of ketoprofen and analgesic effects after topical patch application in rats","volume":"131","author":"Shinkai","year":"2008","journal-title":"J. Control. Release"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1080\/10717540802518082","article-title":"Effect of microneedle on the pharmacokinetics of ketoprofen from its transdermal formulations","volume":"16","author":"So","year":"2009","journal-title":"Drug Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.addr.2003.10.025","article-title":"Penetration enhancers","volume":"56","author":"Williams","year":"2004","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ijpharm.2005.02.014","article-title":"In vitro release of diclofenac diethylamine from caprylocaproyl macrogolglycerides based microemulsions","volume":"296","author":"Djordjevic","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ijpharm.2005.06.023","article-title":"The effect of internal structure of selected water\u2014Tween 40\u00ae\u2014Imwitor 308\u00ae\u2014IPM microemulsions on ketoprofene release","volume":"302","author":"Podlogar","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1590\/s2175-97902017000115012","article-title":"Solid lipid nanoparticles of irbesartan: Preparation, characterization, optimization and pharmacokinetic studies","volume":"53","author":"Soma","year":"2017","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0378-5173(02)00684-1","article-title":"Cosmetic applications for solid lipid nanoparticles (SLN)","volume":"254","author":"Wissing","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jddst.2015.10.003","article-title":"From nanoemulsions to nanostructured lipid carriers: A relevant development in dermal delivery of drugs and cosmetics","volume":"32","author":"Montenegro","year":"2016","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nagai, N., Ogata, F., Ishii, M., Fukuoka, Y., Otake, H., Nakazawa, Y., and Kawasaki, N. (2018). Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072138"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1248\/bpb.b15-00567","article-title":"Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles","volume":"38","author":"Nagai","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1248\/bpb.b13-00630","article-title":"Therapeutic Effects of Gel Ointments containing Tranilast Nanoparticles on Paw Edema in Adjuvant-Induced Arthritis Rats","volume":"37","author":"Nagai","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"337","DOI":"10.5650\/jos.ess14170","article-title":"Topical Therapies for Rheumatoid Arthritis by Gel Ointments containing Indomethacin Nanoparticles in Adjuvant-Induced Arthritis Rat","volume":"64","author":"Nagai","year":"2015","journal-title":"J. Oleo Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.5650\/jos.ess16036","article-title":"Pharmacokinetic Studies of Gel System Containing Ibuprofen Solid Nanoparticles","volume":"65","author":"Nagai","year":"2016","journal-title":"J. Oleo Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1081\/DDC-100100984","article-title":"Permeation enhancers for transdermal drug delivery","volume":"26","author":"Sinha","year":"2000","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1021\/js9701465","article-title":"Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids","volume":"86","author":"Touitou","year":"1997","journal-title":"Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5298","DOI":"10.1038\/s41598-018-23262-0","article-title":"Cold Atmospheric Plasma Induces ATP-Dependent Endocytosis of Nanoparticles and Synergistic U373MG Cancer Cell Death","volume":"8","author":"He","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3109\/03639045.2013.828219","article-title":"Recent advances in gel technologies for topical and transdermal drug delivery","volume":"40","author":"Rehman","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jconrel.2014.03.056","article-title":"Breakthrough discoveries in drug delivery technologies: The next 30 years","volume":"190","author":"Brambilla","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.ejpb.2014.12.020","article-title":"Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: A review","volume":"89","author":"Han","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_26","first-page":"276","article-title":"Transdermal drug delivery: The inherent challenges and technological advancements","volume":"5","author":"Ahad","year":"2010","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9469","DOI":"10.1073\/pnas.0503879102","article-title":"Mechanics of receptor-mediated endocytosis","volume":"102","author":"Gao","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8655","DOI":"10.1021\/acsnano.5b03184","article-title":"Physical Principles of Nanoparticle Cellular Endocytosis","volume":"9","author":"Zhang","year":"2015","journal-title":"ACS Nano"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1021\/nl070363y","article-title":"Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes","volume":"7","author":"Chithrani","year":"2007","journal-title":"Nano Lett."},{"key":"ref_30","first-page":"2274","article-title":"Transdermal drug delivery system: A review","volume":"7","author":"Tanwar","year":"2016","journal-title":"IJPSR"},{"key":"ref_31","first-page":"680","article-title":"Perspective on transdermal drug delivery","volume":"3","author":"Mbah","year":"2011","journal-title":"J. Chem. Pharm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4671","DOI":"10.2174\/092986712803306358","article-title":"Transdermal drug delivery in vitro using diffusion cells","volume":"19","author":"Bartosova","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.2147\/IJN.S173216","article-title":"Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment","volume":"13","author":"Nagai","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1038\/mt.2009.121","article-title":"Fluid phase endocytosis contributes to transfection of DNA by PEI-25","volume":"17","author":"Hufnagel","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1134\/S0012496614060052","article-title":"The effect of dynasore, a blocker of dynamin-dependent endocytosis, on spontaneous quantal and non-quantal release of acetylcholine in murine neuromuscular junctions","volume":"459","author":"Malomouzh","year":"2014","journal-title":"Dokl. Biol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.bbamem.2011.11.020","article-title":"The role of endocytosis on the uptake kinetics of luciferin-conjugated cell-penetrating peptides","volume":"1818","author":"Langel","year":"2012","journal-title":"Biochim. Biophys. Acta Biomembr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/15\/3644\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:09:36Z","timestamp":1760188176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/15\/3644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,25]]},"references-count":36,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["ijms20153644"],"URL":"https:\/\/doi.org\/10.3390\/ijms20153644","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,25]]}}}