{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:25:51Z","timestamp":1791951951256,"version":"4.3.4"},"reference-count":102,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"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: Dry eye disease (DED), also known as \u201ckeratoconjunctivitis sicca\u201d, is a common chronic ocular surface disease accompanied by inflammation and diminished tear production. Bovine Lactoferrin (BLF), a multi-functional iron-binding glycoprotein found in tears, decreased significantly in patients with DED, used for the treatment of dry eye, conjunctivitis, and ocular inflammation. BLF has limited therapeutic efficacy due to poor ocular bioavailability. Methods: This study developed and optimized a BLF-loaded nanosuspension (BLF-NS) using the Box\u2013Behnken Design (BBD). Optimized BLF-NS was then incorporated with polyvinyl pyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) dissolving microneedles (MNs). The formulations were characterized by Scanning and transmission microscopy, DSC, FTIR, ex vivo studies in corneal tissue from sheep and tested for its antibacterial and antifungal efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Aspergillus niger, respectively. Moreover, they were tested for their Benzalkonium chloride (BCL) dry eye in a rabbit model. Results: The optimized nanosuspension showed a vesicle size of (215 \u00b1 0.45) nm, a Z.P (zeta potential) of (\u221228 \u00b1 0.34) mV, and an Entrapment Efficiency (EE%) of (90 \u00b1 0.66) %. The MNs were fabricated using a ratio of biodegradable polymers, PVP\/HPMC. The resulting BLF-NS-MNs exhibited sharp pyramidal geometry with high mechanical strength, ensuring ocular insertion. In vitro release showed 95% lactoferrin release over 24 h, while ex vivo permeation achieved 93% trans-corneal delivery. In vivo, BLF-NS-MNs significantly reduced pro-inflammatory cytokines (TNF-\u03b1, IL-6, MMP-9, IL-1\u03b2, MCP-1) and upregulated antioxidant and anti-inflammatory genes (PPARA, SOD 1), restoring their levels to near-normal (p &lt; 0.001). Conclusions: The nanosuspension combined with MNs has shown higher ocular tolerance against DED ensured by the Draize and Schirmer Tear Test.<\/jats:p>","DOI":"10.3390\/pharmaceutics17050653","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T08:32:29Z","timestamp":1747384349000},"page":"653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Dissolving Microneedles Containing Lactoferrin Nanosuspension for Enhancement of Antimicrobial and Anti-Inflammatory Effects in the Treatment of Dry Eye Disease"],"prefix":"10.3390","volume":"17","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":"Ahmed Mohsen","family":"Faheem","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-3332","authenticated-orcid":false,"given":"Sandra","family":"Hababeh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakline","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Nahda University, Beni-Suef (NUB), Beni-Suef 62511, 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":"Suzan Awad","family":"AbdelGhany Morsy","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria 21561, Egypt"},{"name":"Pathological Sciences Department, MBBS Program, Fakeeh College for Medical Sciences, Jeddah 21461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tassneim M.","family":"Ewedah","sequence":"additional","affiliation":[{"name":"Pharmaceutics and Pharmaceutical Technology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim S.","family":"Mousa","sequence":"additional","affiliation":[{"name":"Pharmaceutics Department, Faculty of Pharmacy, Sinai University, Al-Arish 45511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa A.","family":"Fouad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Deraya University, Minia 61768, Egypt"}],"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 Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.clae.2020.02.009","article-title":"Ocular Conditions and Dry Eye Due to Traditional and New Forms of Smoking: A Review","volume":"43","author":"Makrynioti","year":"2020","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_2","first-page":"CD015448","article-title":"LipiFlow for the Treatment of Dry Eye Disease","volume":"2024","author":"Pucker","year":"2024","journal-title":"Cochrane Database Syst. 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