{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:30:57Z","timestamp":1766579457721,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Education, Culture, Sports, Science, and Technology of Japan","award":["18K06769"],"award-info":[{"award-number":["18K06769"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Materials"],"abstract":"<jats:p>Eye drops containing Tranilast (TL), N-(3,4-dimethoxycinnamoyl) anthramilic acid, are used as an anti-allergic conjunctivitis drug in the ophthalmic field. Traditional eye drops are very patient compliant, although the bioavailability (BA) of most eye drops is low since eye drops cannot be instilled beyond the capacity of the conjunctival sac due to its limited volume. Thus, traditional eye drops have low BA and a short duration of the drug on the ocular surface, so solutions to these problems are highly anticipated. In this study, we designed a sustained-release drug-delivery system (DDS) for TL nanoparticles. TL nanoparticles were prepared by bead mill treatment, and the gel formulations containing TL nanoparticles (TL-NPs-Gel, particle size 50 nm\u2013100 nm) were provided by carboxypolymethylene. The crystal structure of TL with and without bead mill treatment is the same, but the TL solubility in formulations containing nanoparticles was 5.3-fold higher compared with gel formulations containing TL microparticles (TL-MPs-Gel). The photo and thermal stabilities of TL-NPs-Gel are also higher than those of dissolved TL. Moreover, when TL-NPs-Gel is applied to the upper eyelid skin (outside), the TL is released as nanoparticles, and delivered to the lacrimal fluid through the meibomian glands. In addition, the TL release profile for TL-NPs-Gel was sustained over 180 min after the treatment. These findings can be used to develop a sustained-release DDS in the ophthalmic field.<\/jats:p>","DOI":"10.3390\/ma13071675","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T06:10:28Z","timestamp":1586153428000},"page":"1675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles"],"prefix":"10.3390","volume":"13","author":[{"given":"Misa","family":"Minami","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryotaro","family":"Seiriki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Otake","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Nakazawa","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3690-2332","authenticated-orcid":false,"given":"Kazutaka","family":"Kanai","sequence":"additional","affiliation":[{"name":"Department of Small Animal Internal Medicine, School of Veterinary Medicine, University of Kitasato, Towada, Aomori 034-8628, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadatoshi","family":"Tanino","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-Cho, Tokushima 770-8514, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriaki","family":"Nagai","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Baranowski, P., Karolewicz, B., Gajada, M., and Pluta, J. (2014). Ophthalmic Drug Dosage Forms: Characterisation and Research Methods. Sci. World J.","DOI":"10.1155\/2014\/861904"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1208\/s12248-010-9183-3","article-title":"Ocular drug delivery","volume":"12","author":"Gaudana","year":"2010","journal-title":"AAPS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.cis.2015.08.002","article-title":"Mechanistic modelling of ophthalmic drug delivery to the anterior chamber by eye drops and contact lenses","volume":"233","author":"Gause","year":"2016","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ijpharm.2017.09.070","article-title":"Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues","volume":"533","author":"See","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1248\/cpb.55.1002","article-title":"Development of a stick-type transdermal eyelid delivery system of ketotifen fumarate for ophthalmic diseases","volume":"55","author":"Kimura","year":"2007","journal-title":"Chem. Pharm. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1248\/bpb.26.69","article-title":"Drug delivery to the eye with a transdermal therapeutic system","volume":"26","author":"Isowaki","year":"2003","journal-title":"Chem. Pharm. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0168-3659(96)01509-X","article-title":"Transdermal iontophoretic delivery of ketoprofen through human cadaver skin and in humans","volume":"44","author":"Panus","year":"1997","journal-title":"J. Control. Release"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.jconrel.2010.04.013","article-title":"Topical and intravitreous administration of cationic nanoemulsions to deliver antisense oligonucleotides directed towards VEGF KDR receptors to the eye","volume":"145","author":"Hagigit","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.jconrel.2009.04.021","article-title":"Mucoadhesive effect of thiolated PEG stearate and its modified NLC for ocular drug delivery","volume":"137","author":"Shen","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ijpharm.2005.03.033","article-title":"Preparation and characterisation of liposomes encapsulating ketoprofen-cyclodextrin complexes for transdermal drug delivery","volume":"298","author":"Maestrelli","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1002\/mabi.201500192","article-title":"Self-assembly of a multifunctional lipid with core-shell dendrimer DNA nanoparticles enhanced efficient gene delivery at low charge ratios into RPE cells","volume":"15","author":"Sun","year":"2015","journal-title":"Macromol. Biosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1093\/ptj\/83.8.707","article-title":"Phonophoresis versus topical application of ketoprofen: Comparison between tissue and plasma levels","volume":"83","author":"Cagnie","year":"2003","journal-title":"Phys. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jconrel.2008.07.012","article-title":"Yamauchi H. 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_14","doi-asserted-by":"crossref","unstructured":"Katsumi, H., Tanaka, Y., Hitomi, K., Liu, S., Quan, Y.S., Kamiyama, F., Sakane, T., and Yamamoto, A. (2017). Efficient transdermal delivery of alendronate, a nitrogen-containing bisphosphonate, using tip-loaded self-dissolving microneedle arrays for the treatment of osteoporosis. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9030029"},{"key":"ref_15","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. Nanomedicine"},{"key":"ref_16","first-page":"20","article-title":"Hada no seitou to rouka no mechanism","volume":"218","author":"Ebihara","year":"2013","journal-title":"Healthist"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nagai, N., Ogata, F., Yamaguchi, M., Fukuoka, Y., Otake, H., Nakazawa, Y., and Kawasaki, N. (2019). Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153644"},{"key":"ref_18","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_19","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_20","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/sj.ki.5000189","article-title":"Tranilast attenuates connective tissue growth factor-induced extracellular matrix accumulation in renal cells","volume":"69","author":"Qi","year":"2006","journal-title":"Kidney Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1902\/jop.2004.75.8.1054","article-title":"Effect of tranilast on matrix metalloproteinase-1 secretion from human gingival fibroblasts in vitro","volume":"75","author":"Maita","year":"2004","journal-title":"J. Periodontol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1159\/000063884","article-title":"Effect of tranilast on proliferation, collagen gel contraction, and transforming growth factor beta secretion of retinal pigment epithelial cells and fibroblasts","volume":"34","author":"Yasukawa","year":"2002","journal-title":"Ophthalmic Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1111\/j.1365-2222.1992.tb00146.x","article-title":"Inhibition of proliferative responses of lymphocytes to food antigens by an anti-allergic drug, N(30,40-dimethoxycinnamoyl) anthranilic acid (Tranilast) in children with atopic dermatitis","volume":"22","author":"Kondo","year":"1992","journal-title":"Clin. Exp. Allergy"},{"key":"ref_24","first-page":"2471","article-title":"Therapeutic potential of tranilast, an anti-allergy drug, in proliferative disorders","volume":"32","author":"Rogosnitzky","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1254\/fpj.101.1_27","article-title":"Effect of tranilast ophthalmic solution on allergic conjunctivitis in guinea pigs","volume":"101","author":"Itoh","year":"1993","journal-title":"Nihon Yakurigaku Zasshi"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1016\/j.jcrs.2007.07.041","article-title":"Safety and efficacy of intracapsular tranilast microspheres in experimental posterior capsule opacification","volume":"33","author":"Wang","year":"2007","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/00003226-200005000-00021","article-title":"Inhibitory effects of tranilast on the proliferation and functions of human pterygiumderived fibroblasts","volume":"19","author":"Isaji","year":"2000","journal-title":"Cornea"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.jcrs.2004.09.056","article-title":"Effects of topical tranilast on corneal haze after photorefractive keratectomy","volume":"31","author":"Song","year":"2005","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S457","DOI":"10.3928\/1081-597X-19970801-20","article-title":"Effect of topical tranilast and corticosteroids on subepithelial haze after photorefractive keratectomy in rabbits","volume":"13","author":"Furukawa","year":"1997","journal-title":"J. Refract. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1167\/iovs.06-0775","article-title":"Slow-releasing tranilast in polytetrafluoroethylene\/polylactide-co-glycolide laminate delays adjustment after strabismus surgery in rabbit model","volume":"48","author":"Lee","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"177","DOI":"10.5650\/jos.ess13082","article-title":"Improved corneal toxicity and permeability of tranilast by the preparation of ophthalmic formulations containing its nanoparticles","volume":"63","author":"Nagai","year":"2014","journal-title":"J. Oleo Sci."},{"key":"ref_32","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_33","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.2147\/IJN.S196681","article-title":"Energy-dependent endocytosis is responsible for drug transcorneal penetration following the instillation of ophthalmic formulations containing indomethacin nanoparticles","volume":"14","author":"Nagai","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cap.2005.01.012","article-title":"Role of polymeric stabilizers for drug nanocrystal dispersions","volume":"5","author":"Choi","year":"2005","journal-title":"Curr. Appl. Phys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.ejps.2009.12.009","article-title":"Novel crystalline solid dispersion of tranilast with high photostability and improved oral bioavailability","volume":"39","author":"Kawabata","year":"2010","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0014-4835(61)80006-7","article-title":"The oily layer of the tear film and evaporation from the corneal surface","volume":"1","author":"Mishima","year":"1961","journal-title":"Exp. Eye Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Nagai, N., Ishii, M., Seiriki, R., Ogata, F., Otake, H., Nakazawa, Y., Okamoto, N., Kanai, K., and Kawasaki, N. (2020). Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles. 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