{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:45:43Z","timestamp":1792478743389,"version":"4.5.0"},"reference-count":129,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"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\/Objectives: Allergic conjunctivitis (AC) is the most common inflammatory disease affecting the ocular conjunctiva. Tacrolimus (TCR), a potent calcineurin inhibitor, is limited by poor aqueous solubility and low ocular bioavailability. This study aimed to develop TCR-loaded cubosomes (TCR-Cubs) incorporated into HPMC\/PVP K90 dissolving microneedles (MNs) to enhance their therapeutic efficacy. Methods: TCR-Cubs were prepared using a modified top-down fragmentation method with glyceryl monooleate and poloxamer 407, optimized via Box\u2013Behnken design, and incorporated into dissolving MNs. The system was evaluated in vitro, ex vivo, and in vivo using a rabbit model of allergic conjunctivitis. Results: The optimized formulation exhibited the smallest particle size (210 \u00b1 0.91 nm), polydispersity index (0.29 \u00b1 0.03), zeta potential (\u221221 \u00b1 0.87 mV), and the highest entrapment efficiency (% 93.3 \u00b1 0.45). The optimized formulation was incorporated into MNs via micro molding. Scanning electron microscopy (SEM) confirmed well-defined, sharp microneedles, with low height reduction (&lt;10%) by mechanical testing and high penetration efficiency (&gt;85\u201390%). In vitro release studies revealed sustained drug release of (~75\u201380%) over 24 h, compared to (~40%) from the TCR suspension, following diffusion-controlled kinetics. Ex vivo permeation studies showed a (~2\u20133-fold) enhancement in corneal drug flux. In vivo pharmacodynamic evaluation using an ovalbumin-induced allergic conjunctivitis model demonstrated significant reductions in inflammatory mediators, including inflammatory markers (TNF-\u03b1, IL-1\u03b2, IL-6, NLRP3), which were reduced by (~50\u201375%), with modulation of CPA3, BCL2, and TGF-\u03b21 by qRT-PCR. Histopathology and TLR4 analysis confirmed reduced inflammation without irritation. Conclusions: This dual-delivery system offers a promising, non-invasive platform for enhanced ocular delivery of tacrolimus with superior anti-inflammatory efficacy in allergic conjunctivitis.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040459","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:21:32Z","timestamp":1775737292000},"page":"459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Innovative HPMC\/PVP K90 Dissolving Microneedles Incorporating Tacrolimus-Loaded Cubosomes: A Novel Strategy for Managing Allergic Conjunctivitis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7970-2288","authenticated-orcid":false,"given":"Sammar Fathy","family":"Elhabal","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai S.","family":"Shoela","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3985-8931","authenticated-orcid":false,"given":"Fatma E.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Physiology, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia"},{"name":"Medical Physiology Department, Faculty of Medicine, Cairo University, Kasr Alainy, Giza 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5874-194X","authenticated-orcid":false,"given":"Suzan","family":"Awad AbdelGhany Morsy","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt"},{"name":"Pathological Sciences Department, MBBS Program, Fakeeh College for Medical Sciences, Jeddah 21461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5633-4128","authenticated-orcid":false,"given":"Shady","family":"Allam","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, Menoufia 32811, Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia National University, Cairo-Alexandria Agricultural Road, Menoufia 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7717-3925","authenticated-orcid":false,"given":"Reem Abd Elhameed","family":"Aldeeb","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8477-4027","authenticated-orcid":false,"given":"Amal Anwar","family":"Taha","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania","family":"Mostafa Abd El Galil","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1265-9227","authenticated-orcid":false,"given":"Amr","family":"M. Emam","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahla A.","family":"Elzohairy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt"},{"name":"Air Force Specialized Hospital, Cairo 19448, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanaa","family":"Wanas","sequence":"additional","affiliation":[{"name":"Medical Pharmacology Department, Faculty of Medicine, Cairo University, Cairo 11956, Egypt"},{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy, Taibah University, Madinah 41477, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4930-792X","authenticated-orcid":false,"given":"Ahmed Mohsen Elsaid","family":"Hamdan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"},{"name":"Prince Fahad bin Sultan Chair for Biomedical Research (PFSCBR), Tabuk 74191, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1007\/s13346-025-01796-x","article-title":"Nano-Spanlastics-Loaded Dissolving Microneedle Patches for Ketotifen Fumarate: Advanced Strategies for Allergic Conjunctivitis Treatment and Molecular Insights","volume":"15","author":"Elhabal","year":"2025","journal-title":"Drug Deliv. 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