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Res."],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Fungal keratitis (FK), caused by fungi like\n                    <jats:italic>Aspergillus<\/jats:italic>\n                    ,\n                    <jats:italic>Fusarium<\/jats:italic>\n                    , and\n                    <jats:italic>Candida<\/jats:italic>\n                    , accounts for 20\u201360% of microbial keratitis cases and over 1\u00a0million visual impairments annually. Voriconazole (VOR) is effective against FK, but its eye drop formulations suffer from poor bioavailability, while intrastromal injections are invasive and carry risks. This study aimed to address these challenges by formulating a VOR nanosuspension (NS) and fabricating an ocular bilayer dissolving microneedle array patch (dMAP) incorporating the VOR NS for localized drug delivery to the cornea. The VOR NS was prepared using an aqueous media milling method with polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) as stabilizer and cryoprotectant, resulting in stable nanosized particles with a mean size of 270.11\u2009\u00b1\u20095.82\u00a0nm and a PDI of 0.217\u2009\u00b1\u20090.019. The formulation demonstrated a 1.71-fold increase in saturation solubility and a high drug content (72.5%). Both VOR NS and free VOR were incorporated into the MAP tips using a two-layer casting method. The VOR NS-loaded bilayer dMAP exhibited higher drug content (118.84\u2009\u00b1\u200920.67\u00a0\u00b5g) compared to the free VOR-loaded bilayer dMAP (83.08\u2009\u00b1\u20092.69\u00a0\u00b5g). Additionally, they demonstrated superior mechanical strength, greater insertion depth (~\u2009390\u00a0\u03bcm), and faster tip dissolution in excised porcine corneal tissue (~\u20095\u00a0min) compared to the free VOR-loaded bilayer dMAP. Ex vivo studies showed that the VOR NS-loaded bilayer dMAP deposited 47.38\u2009\u00b1\u20098.08\u00a0\u00b5g of drug into the porcine cornea, 2.31 times more than the free VOR-loaded bilayer dMAP (20.43\u2009\u00b1\u20096.11\u00a0\u00b5g), closely approximating the clinical dose used in VOR intrastromal injections (50\u00a0\u00b5g\/0.1 mL). Furthermore, the disc diffusion assay revealed that VOR NS and VOR NS-loaded bilayer dMAP had greater antifungal activity against\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    and\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    compared to free VOR and free VOR-loaded bilayer dMAP. Biocompatibility was confirmed through a human corneal epithelial cell viability assay, and ocular irritation potential was evaluated using the HET-CAM assay, revealing a safe and non-irritant profile. Thus, this innovative NS-MAP hybrid system offers efficient drug delivery with minimal invasiveness and could potentially improve therapeutic outcomes in the management of FK.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s13346-025-02021-5","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T14:36:12Z","timestamp":1765290972000},"page":"1164-1187","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Voriconazole nanosuspension-loaded ocular bilayer dissolving microneedle patch for the management of fungal keratitis"],"prefix":"10.1007","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0754-0192","authenticated-orcid":false,"given":"B.H. Jaswanth","family":"Gowda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9010-0739","authenticated-orcid":false,"given":"Anjali K.","family":"Pandya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4312-771X","authenticated-orcid":false,"given":"Shilpkala","family":"Gade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7502-1279","authenticated-orcid":false,"given":"Ross","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0414-8972","authenticated-orcid":false,"given":"Alejandro J.","family":"Paredes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9226-9984","authenticated-orcid":false,"given":"Mohammed Gulzar","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3151-2565","authenticated-orcid":false,"given":"Yiwei","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0766-4147","authenticated-orcid":false,"given":"Ryan F.","family":"Donnelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7582-2082","authenticated-orcid":false,"given":"Raghu Raj Singh","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-9066","authenticated-orcid":false,"given":"Lalitkumar K.","family":"Vora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"2021_CR1","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.jtos.2021.12.001","volume":"24","author":"N Sharma","year":"2022","unstructured":"Sharma N, Bagga B, Singhal D, Nagpal R, Kate A, Saluja G, et al. Fungal keratitis: A review of clinical presentations, treatment strategies and outcomes. Ocul Surf. 2022;24:22\u201330.","journal-title":"Ocul Surf"},{"key":"2021_CR2","doi-asserted-by":"crossref","unstructured":"Brown L, Leck AK, Gichangi M, Burton MJ, Denning DW. The global incidence and diagnosis of fungal keratitis. Lancet Infect Dis. 2021 [cited 2023 Feb 10];21:e49\u201357. Available from: http:\/\/www.thelancet.com\/article\/S1473309920304485\/fulltext","DOI":"10.1016\/S1473-3099(20)30448-5"},{"key":"2021_CR3","doi-asserted-by":"crossref","unstructured":"Awad R, Ghaith AA, Awad K, Saad MM, Elmassry AA. Fungal Keratitis: Diagnosis, Management, and Recent Advances. Clin Ophthalmol. 2024 [cited 2025 Apr 17];18:85\u2013106. 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Ryan F. Donnelly, through his university, has licensed patents on specific microneedle platforms to individual companies and has provided consultancy advice to companies developing microneedle-based products on a case-by-case basis. The microneedle systems described in this manuscript are not covered by any patent (out-licensed or otherwise) held by Ryan F. Donnelly, nor does he provide consultancy advice to any company developing microneedle technologies for ocular delivery of voriconazole or any other antifungal drug. Accordingly, Ryan F. Donnelly declares no conflict of interest in relation to this work. The other authors declare no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}