{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:29:22Z","timestamp":1786364962244,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"publisher","award":["25K10060"],"award-info":[{"award-number":["25K10060"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25K10060"],"award-info":[{"award-number":["25K10060"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Dry eye disease (DED) is a multifactorial disorder characterized by tear film instability, inflammation, and ocular surface damage, which significantly impairs visual function and quality of life. Conventional ophthalmic formulations, such as eye drops, have low bioavailability owing to rapid elimination, necessitating frequent administration. In this study, we developed an eyelid-applied drug delivery system (DDS) based on troxipide (TRO) nanoparticle formulation (TRO-NP@EG) to achieve sustained ocular surface delivery. Methods: TRO nanosuspensions were prepared by wet bead milling and incorporated into a Carbopol-based gel. Particle size, dispersion stability, and uniformity were evaluated, and in vitro drug release studies was compared with that of TRO-MP@EG. In vivo drug transfer into tear fluid was assessed in rabbits following eyelid application, and therapeutic efficacy was evaluated in an N-acetylcysteine-induced dry eye model. Results: TRO nanosuspensions had a mean particle size of approximately 118 nm. TRO-NP@EG exhibited superior dispersion stability and uniformity and achieved 2.5-fold higher drug release than TRO-MP@EG, while the nanoparticles remained in solid form. In vivo studies in rabbits, TRO-NP@EG significantly enhanced drug transfer into tear fluid, primarily via the meibum pathway. Furthermore, TRO-NP@EG significantly improved mucin levels, tear secretion, and tear film stability compared with TRO-MP@EG in an N-acetylcysteine-induced dry eye model. Conclusions: These findings suggest that eyelid application of nanoparticle-based formulations enables efficient and sustained drug delivery to the ocular surface via the meibomian glands. Therefore, TRO-NP@EG represents a promising therapeutic strategy for DED, providing enhanced efficacy and a novel route of administration for ophthalmic DDSs.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080973","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:09Z","timestamp":1786361889000},"page":"973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Meibomian Gland-Mediated Drug Delivery via Eyelid Application of Troxipide Nanoparticles Improves an N-Acetylcysteine-Induced Dry Eye"],"prefix":"10.3390","volume":"18","author":[{"given":"Hiroko","family":"Otake","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2755-8341","authenticated-orcid":false,"given":"Fumihiko","family":"Ogata","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manju","family":"Misra","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pham. Technology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, GJ 380009, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 II, School of Veterinary Medicine, Kitasato University, 35-1 Higashi 23 ban-cho, Towada 034-8628, Aomori, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanobu","family":"Tsubaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacotherapy, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki 769-2193, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-3204","authenticated-orcid":false,"given":"Naoki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"University Startup Promotion Center, Research Promotion Headquarters, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan"},{"name":"Department of Pharmaceutical Engineering, Faculty of Engineering, Sanyo-Onoda City University, 1-1-1 Daigaku-dori, Sanyo-Onoda 756-0884, Yamaguchi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9412-0868","authenticated-orcid":false,"given":"Naohito","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1266-038X","authenticated-orcid":false,"given":"Noriaki","family":"Nagai","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108115","DOI":"10.1016\/j.exer.2020.108115","article-title":"Biological functions of tear film","volume":"197","author":"Pflugfelder","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/978-1-4615-2417-5_41","article-title":"Structure and function of the tear film","volume":"350","author":"Dilly","year":"1994","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jtos.2017.05.006","article-title":"TFOS DEWS II Management and Therapy Report","volume":"15","author":"Jones","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"758397","DOI":"10.1155\/2010\/758397","article-title":"Troxipide in the management of gastritis: A randomized comparative trial in general practice","volume":"2010","author":"Dewan","year":"2010","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.3109\/03639045.2014.956113","article-title":"Preparation and pharmacokinetics study on gastro-floating sustained-release tablets of troxipide","volume":"41","author":"Gao","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1023\/A:1005656916830","article-title":"Diclofenac-induced gastric mucosal fluorescence in rats","volume":"46","author":"Matsui","year":"2001","journal-title":"Dig. Dis. Sci."},{"key":"ref_8","first-page":"757","article-title":"Effects of troxipide on the prednisolone-induced aggravation of gastric mucosal lesions occurred by HC1 in rats","volume":"33","author":"Inoue","year":"2005","journal-title":"Jpn. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1089\/jop.1986.2.67","article-title":"Topical ocular drug delivery: Recent developments and future challenges","volume":"2","author":"Lee","year":"1986","journal-title":"J. Ocul. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1089\/jop.2012.0200","article-title":"Novel strategies for anterior segment ocular drug delivery","volume":"29","author":"Cholkar","year":"2013","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.2165\/00003088-199018040-00001","article-title":"Ocular drug delivery. Pharmacokinetic considerations","volume":"18","author":"Schoenwald","year":"1990","journal-title":"Clin. Pharmacokinet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1186\/s12951-023-01992-2","article-title":"Nanotechnology-based ocular drug delivery systems: Recent advances and future prospects","volume":"21","author":"Li","year":"2023","journal-title":"J. Nanobiotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114582","DOI":"10.1016\/j.addr.2022.114582","article-title":"Novel drug delivery systems for the management of dry eye","volume":"191","author":"Nagai","year":"2022","journal-title":"Adv. Drug. Deliv. Rev."},{"key":"ref_14","first-page":"12422","article-title":"Nanosuspensions in ophthalmology: Overcoming challenges and enhancing drug delivery for eye diseases","volume":"658","author":"Arkaban","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.addr.2005.07.005","article-title":"The use of mucoadhesive polymers in ocular drug delivery","volume":"57","author":"Ludwig","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.ejps.2013.07.002","article-title":"Developing an in situ nanosuspension: A novel approach towards the efficient administration of poorly soluble drugs at the anterior eye","volume":"50","author":"Luschmann","year":"2013","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.31083\/ph.2011.0358","article-title":"Development of a novel ophthalmic ciclosporin A-loaded nanosuspension using top-down media milling methods","volume":"66","author":"Kim","year":"2011","journal-title":"Pharmazie"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2217\/17435889.2.1.11","article-title":"Ocular drug delivery: Nanomedicine applications","volume":"2","author":"Vandervoort","year":"2007","journal-title":"Nanomedicine"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bachu, R.D., Chowdhury, P., Al-Saedi, Z.H.F., Karla, P.K., and Boddu, S.H.S. (2018). Ocular drug delivery barriers-role of nanocarriers in the treatment of anterior segment ocular diseases. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10010028"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s11095-018-2556-5","article-title":"Ocular pharmacokinetics of a topical ophthalmic nanomicellar solution of cyclosporine (Cequa\u00ae) for dry eye disease","volume":"36","author":"Mandal","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_21","first-page":"721","article-title":"The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine","volume":"90","author":"Sheffner","year":"1964","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_22","first-page":"2958","article-title":"Effects of acetylcysteine on rabbit conjunctival and corneal surfaces. A sccaning electron microscopy study","volume":"32","author":"Thermes","year":"1991","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/978-1-4615-5359-5_36","article-title":"Mucous contribution to rat tear-film thickness measured with a microelectrode technique","volume":"438","author":"Anderton","year":"1998","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0014-5793(00)01464-2","article-title":"N-Acetylcysteine suppresses TNF-induced NF-kappaB activation through inhibition of IkappaB kinases","volume":"472","author":"Oka","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1046\/j.1432-1327.2000.01194.x","article-title":"Epidermal growth factor receptor is modulated by redox through multiple mechanisms. Effects of reductants and H2O2","volume":"267","author":"Kamata","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"33018","DOI":"10.1074\/jbc.271.51.33018","article-title":"Suppression of nerve growth factor-induced neuronal differentiation of PC12 cells. N-acetylcysteine uncouples the signal transduction from ras to the mitogen-activated protein kinase cascade","volume":"271","author":"Kamata","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40780-026-00542-w","article-title":"Troxipide nanosuspensions prevent indomethacin-induced gastrointestinal lesions in adjuvant-induced arthritis rats","volume":"12","author":"Fujimoto","year":"2026","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.2147\/DDDT.S433776","article-title":"Therapeutic effects of hydrogel formulations incorporating troxipide nanoparticles on oral mucositis in hamsters","volume":"17","author":"Kadowaki","year":"2023","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.tox.2014.02.012","article-title":"A nanoparticle formulation reduces the corneal toxicity of indomethacin eye drops and enhances its corneal permeability","volume":"319","author":"Nagai","year":"2014","journal-title":"Toxicology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s40780-024-00375-5","article-title":"Enhancement of therapeutic efficacy of brinzolamide for glaucoma by nanocrystallization and tyloxapol addition","volume":"10","author":"Masuda","year":"2024","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Nagai, N., Minami, M., Deguchi, S., Otake, H., Sasaki, H., and Yamamoto, N. (2020). An in situ gelling system based on methylcellulose and tranilast solid nanoparticles enhances ocular residence time and drug absorption into the cornea and conjunctiva. Front. Bioeng. Biotechnol., 8.","DOI":"10.3389\/fbioe.2020.00764"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.5650\/jos.ess24160","article-title":"Therapeutic effects of rebamipide nanocrystals as carbopol gel formulation containing gum arabic in a hamster model of oral mucositis","volume":"73","author":"Otake","year":"2024","journal-title":"J. Oleo Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.2147\/DDDT.S469445","article-title":"Copolymerized polymers based on cyclodextrins and cationic groups enhance therapeutic effect of rebamipide in the N-acetylcysteine-treated dry eye model","volume":"18","author":"Otake","year":"2024","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_34","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. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020155"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s40199-018-00235-2","article-title":"Formation of nanosuspensions in bottom-up approach: Theories and optimization","volume":"27","author":"Tehrani","year":"2019","journal-title":"DARU J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nrd1494","article-title":"Nanosuspensions in drug delivery","volume":"3","author":"Rabinow","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1208\/s12249-023-02516-9","article-title":"Ocular drug delivery: A comprehensive review","volume":"24","author":"Ahmed","year":"2023","journal-title":"AAPS PharmSciTech"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.11648\/j.pst.20200401.11","article-title":"Novel long retentive posaconazole ophthalmic suspension","volume":"4","author":"Simta","year":"2020","journal-title":"Pharma. Sci. Tech."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ijpharm.2007.01.019","article-title":"Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor","volume":"338","author":"Aggarwal","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1167\/iovs.10-6997c","article-title":"The international workshop on meibomian gland dysfunction: Report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland","volume":"52","author":"Knop","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nagai, N., Ogata, F., Kadowaki, R., Deguchi, S., Otake, H., Nakazawa, Y., Nagata, M., Sasaki, H., and Kawasaki, N. (2023). Orally disintegrating tablets containing famotidine nanoparticles provide high intestinal absorbability via the energy-dependent endocytosis pathway. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1167291"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Otake, H., Yamaguchi, M., Ogata, F., Deguchi, S., Yamamoto, N., Sasaki, H., Kawasaki, N., and Nagai, N. (2021). Energy-dependent endocytosis is responsible for skin penetration of formulations based on a combination of indomethacin nanoparticles and l-menthol in rat and g\u00f6ttingen minipig. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105137"},{"key":"ref_43","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."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:42:09Z","timestamp":1786362129000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18080973"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18080973","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]}}}