{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:11:31Z","timestamp":1777594291596,"version":"3.51.4"},"reference-count":83,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T00:00:00Z","timestamp":1634256000000},"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>Dry eye disease (DED) is a high prevalent multifactorial disease characterized by a lack of homeostasis of the tear film which causes ocular surface inflammation, soreness, and visual disturbance. Conventional ophthalmic treatments present limitations such as low bioavailability and side effects. Lactoferrin (LF) constitutes a promising therapeutic tool, but its poor aqueous stability and high nasolacrimal duct drainage hinder its potential efficacy. In this study, we incorporate lactoferrin into hyaluronic acid coated liposomes by the lipid film method, followed by high pressure homogenization. Pharmacokinetic and pharmacodynamic profiles were evaluated in vitro and ex vivo. Cytotoxicity and ocular tolerance were assayed both in vitro and in vivo using New Zealand rabbits, as well as dry eye and anti-inflammatory treatments. LF loaded liposomes showed an average size of 90 nm, monomodal population, positive surface charge and a high molecular weight protein encapsulation of 53%. Biopharmaceutical behaviour was enhanced by the nanocarrier, and any cytotoxic effect was studied in human corneal epithelial cells. Developed liposomes revealed the ability to reverse dry eye symptoms and possess anti-inflammatory efficacy, without inducing ocular irritation. Hence, lactoferrin loaded liposomes could offer an innovative nanotechnological tool as suitable approach in the treatment of DED.<\/jats:p>","DOI":"10.3390\/pharmaceutics13101698","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T23:05:47Z","timestamp":1634511947000},"page":"1698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Development of Lactoferrin-Loaded Liposomes for the Management of Dry Eye Disease and Ocular Inflammation"],"prefix":"10.3390","volume":"13","author":[{"given":"Ana","family":"L\u00f3pez-Machado","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-015X","authenticated-orcid":false,"given":"Natalia","family":"D\u00edaz-Garrido","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Physiology, Faculty of Pharmacy & Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain"},{"name":"Sant Joan de D\u00e9u Research Institute (IR-SJD), 08950 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-4283","authenticated-orcid":false,"given":"Amanda","family":"Cano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1269-3847","authenticated-orcid":false,"given":"Marta","family":"Espina","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"}]},{"given":"Josefa","family":"Badia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Physiology, Faculty of Pharmacy & Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain"},{"name":"Sant Joan de D\u00e9u Research Institute (IR-SJD), 08950 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-269X","authenticated-orcid":false,"given":"Laura","family":"Baldom\u00e0","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Physiology, Faculty of Pharmacy & Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain"},{"name":"Sant Joan de D\u00e9u Research Institute (IR-SJD), 08950 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-4821","authenticated-orcid":false,"given":"Ana Cristina","family":"Calpena","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9737-6017","authenticated-orcid":false,"given":"Eliana B.","family":"Souto","sequence":"additional","affiliation":[{"name":"Centre of Biological Engineering (CEB), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal"}]},{"given":"Mar\u00eda Luisa","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2571-108X","authenticated-orcid":false,"given":"Elena","family":"S\u00e1nchez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, 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Surf."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Roda, M., Corazza, I., Reggiani, M.L.B., Pellegrini, M., Taroni, L., Giannaccare, G., and Versura, P. (2020). Dry Eye Disease and Tear Cytokine Levels\u2014A Meta-Analysis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093111"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Agarwal, P., Craig, J., and Rupenthal, I. (2021). Formulation Considerations for the Management of Dry Eye Disease. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13020207"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-74159-w","article-title":"A novel serine protease inhibitor as potential treatment for dry eye syndrome and ocular inflammation","volume":"10","author":"Joossen","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e412","DOI":"10.1111\/aos.13526","article-title":"Dry eye disease and oxidative stress","volume":"96","author":"Seen","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mazet, R., Yam\u00e9ogo, J.B.G., Wouessidjewe, D., Choisnard, L., and G\u00e8ze, A. (2020). Recent Advances in the Design of Topical Ophthalmic Delivery Systems in the Treatment of Ocular Surface Inflammation and Their Biopharmaceutical Evaluation. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12060570"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fphar.2017.00173","article-title":"Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies","volume":"8","author":"Anfuso","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.survophthal.2015.07.001","article-title":"The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management","volume":"61","author":"Foster","year":"2016","journal-title":"Surv. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jaad.2016.02.1241","article-title":"Prevention and management of glucocorticoid-induced side effects: A comprehensive review","volume":"76","author":"Caplan","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1097\/00055735-200012000-00016","article-title":"Ocular complications of topical, peri-ocular, and systemic corticosteroids","volume":"11","author":"Carnahan","year":"2000","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.ijbiomac.2016.10.087","article-title":"Characteristics of bovine lactoferrin powders produced through spray and freeze drying processes","volume":"95","author":"Wang","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_12","first-page":"301.e1","article-title":"Lactoferrin: Structure, function and applications","volume":"33","year":"2009","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1089\/ten.tea.2020.0015","article-title":"Bioactive Membrane Immobilized with Lactoferrin for Modulation of Bone Regeneration and Inflammation","volume":"26","author":"Lee","year":"2020","journal-title":"Tissue Eng. Part A"},{"key":"ref_14","first-page":"1","article-title":"Lactoferrin and Its biological functions","volume":"66","author":"Kanyshkova","year":"2001","journal-title":"Biochemestry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11095-019-2569-8","article-title":"Review of Biomarkers in Ocular Matrices: Challenges and Opportunities","volume":"36","author":"Tamhane","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.3389\/fimmu.2019.01178","article-title":"Tear Lactoferrin and Lysozyme as Clinically Relevant Biomarkers of Mucosal Immune Competence","volume":"10","author":"Hanstock","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"883","DOI":"10.3109\/02713683.2015.1075220","article-title":"Lactoferrin Expression in Human and Murine Ocular Tissue","volume":"41","author":"Rageh","year":"2016","journal-title":"Curr. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Lu, C., and Zhang, J. (2021). Lactoferrin and Its Detection Methods: A Review. Nutrients, 13.","DOI":"10.3390\/nu13082492"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rosa, L., Cutone, A., Lepanto, M.S., Paesano, R., and Valenti, P. (2017). Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091985"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) (2012). Scientific Opinion on bovine lactoferrin. EFSA J., 10, 1\u201326.","DOI":"10.2903\/j.efsa.2012.2811"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0008-8749(03)00006-6","article-title":"\u00c5; Mattsby-Baltzer, I. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-\u03baB","volume":"220","author":"Ohlsson","year":"2002","journal-title":"Cell. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10915","DOI":"10.1021\/bi8012164","article-title":"The N1 Domain of Human Lactoferrin Is Required for Internalization by Caco-2 Cells and Targeting to the Nucleus","volume":"47","author":"Suzuki","year":"2008","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.jff.2016.06.013","article-title":"Bovine lactoferrin-derived ACE inhibitory tripeptide LRP also shows antioxidative and anti-inflammatory activities in endothelial cells","volume":"25","author":"Gu","year":"2016","journal-title":"J. Funct. Foods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mehy.2017.03.029","article-title":"Iron chelation for the treatment of uveitis","volume":"103","author":"Chen","year":"2017","journal-title":"Med. Hypotheses"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9703","DOI":"10.3390\/molecules20069703","article-title":"Multifunctional Iron Bound Lactoferrin and Nanomedicinal Approaches to Enhance Its Bioactive Functions","volume":"20","author":"Kanwar","year":"2015","journal-title":"Molecules"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.colsurfb.2016.04.054","article-title":"PEGylated PLGA nanospheres optimized by design of experiments for ocular administration of dexibuprofen\u2014In vitro, ex vivo and in vivo characterization","volume":"145","author":"Egea","year":"2016","journal-title":"Colloids Surfaces B: Biointerfaces"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kumari, S., Dandamudi, M., Rani, S., Behaeghel, E., Behl, G., Kent, D., O\u2019Reilly, N., O\u2019Donovan, O., McLoughlin, P., and Fitzhenry, L. (2021). Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060905"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1016\/j.jconrel.2017.03.046","article-title":"Polymeric nanoparticles of (-)-epigallocatechin gallate: A new formulation for the treatment of ocular diseases","volume":"259","author":"Cano","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S0022-2836(65)80093-6","article-title":"Diffusion of univalent ions across the lamellae of swollen phospholipids","volume":"13","author":"Bangham","year":"1965","journal-title":"J. Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lebr\u00f3n, J.A., L\u00f3pez-L\u00f3pez, M., Garc\u00eda-Calder\u00f3n, C.B., Rosado, I.V., Balestra, F.R., Huertas, P., Rodik, R.V., Kalchenko, V.I., Bernal, E., and Moy\u00e1, M.L. (2021). Multivalent Calixarene-Based Liposomes as Platforms for Gene and Drug Delivery. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081250"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Navarro-Partida, J., Castro-Castaneda, C., Cruz-Pavlovich, F.S., Aceves-Franco, L., Guy, T., and Santos, A. (2021). Lipid-Based Nanocarriers as Topical Drug Delivery Systems for Intraocular Diseases. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13050678"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.1021\/nl102184c","article-title":"Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications","volume":"10","author":"Shi","year":"2010","journal-title":"Nano Lett."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rao, N., Rho, J.G., Um, W., Ek, P.K., Nguyen, V.Q., Oh, B.H., Kim, W., and Park, J.H. (2020). Hyaluronic Acid Nanoparticles as Nanomedicine for Treatment of Inflammatory Diseases. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12100931"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lu, W.-L., and Qi, X.-R. (2021). Preparation of Drug Liposomes by Thin-Film Hydration and Homogenization. Liposome-Based Drug Delivery Systems, Springer.","DOI":"10.1007\/978-3-662-49320-5"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"124","DOI":"10.3109\/03639045.2013.850709","article-title":"Media milling process optimization for manufacture of drug nanoparticles using design of experiments (DOE)","volume":"41","author":"Nekkanti","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1007\/s12274-020-2940-4","article-title":"New approach for time-resolved and dynamic investigations on nanoparticles agglomeration","volume":"13","author":"Anaraki","year":"2020","journal-title":"Nano Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.ijpharm.2018.05.050","article-title":"Development of fluorometholone-loaded PLGA nanoparticles for treatment of inflammatory disorders of anterior and posterior segments of the eye","volume":"547","author":"Calpena","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_38","unstructured":"Aguilar, M.-I. (2004). HPLC of Peptides and Proteins. Methods and Protocols, Humana Press. [1st ed.]."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.nano.2018.01.019","article-title":"Epigallocatechin-3-gallate loaded PEGylated-PLGA nanoparticles: A new anti-seizure strategy for temporal lobe epilepsy","volume":"14","author":"Cano","year":"2018","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jconrel.2019.03.010","article-title":"Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)\/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe\/PS1dE9 Alzheimer\u2019s disease mice model","volume":"301","author":"Cano","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.2217\/nnm-2019-0201","article-title":"Ocular penetration of fluorometholone-loaded PEG-PLGA nanoparticles functionalized with cell-penetrating peptides","volume":"14","author":"Parrotta","year":"2019","journal-title":"Nanomedicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.tiv.2017.05.024","article-title":"HET-CAM test. Application to shampoos in developing countries","volume":"45","author":"Derouiche","year":"2017","journal-title":"Toxicol. Vitr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1007\/s12274-016-1310-8","article-title":"Catheters coated with Zn-doped CuO nanoparticles delay the onset of catheter-associated urinary tract infections","volume":"10","author":"Shalom","year":"2016","journal-title":"Nano Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Li, C., Song, Y., Luan, S., Wan, P., Li, N., Tang, J., Han, Y., Xiong, C., and Wang, Z. (2012). Research on the Stability of a Rabbit Dry Eye Model Induced by Topical Application of the Preservative Benzalkonium Chloride. PLOS ONE, 7.","DOI":"10.1371\/annotation\/f2df1a21-1df3-4c2d-a99a-b054dfbc6443"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.2174\/138161209788923886","article-title":"Nanocarriers in Ocular Drug Delivery: An Update Review","volume":"15","author":"Wadhwa","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1016\/j.xphs.2017.05.022","article-title":"Delivery of Riboflavin-5\u2032-Monophosphate Into the Cornea: Can Liposomes Provide Any Enhancement Effects?","volume":"106","author":"Kandzija","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ijpharm.2013.11.025","article-title":"Design of cationic lipid nanoparticles for ocular delivery: Development, characterization and cytotoxicity","volume":"461","author":"Fangueiro","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"119835","DOI":"10.1016\/j.ijpharm.2020.119835","article-title":"Curcumin-loaded proniosomal gel as a biofreindly alternative for treatment of ocular inflammation: In-vitro and in-vivo assessment","volume":"589","author":"Aboali","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.foodhyd.2018.11.030","article-title":"Liposomal vesicles-protein interaction: Influences of iron liposomes on emulsifying properties of whey protein","volume":"89","author":"Yi","year":"2019","journal-title":"Food Hydrocoll."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Mazyed, E.A., and Abdelaziz, A.E. (2020). Fabrication of Transgelosomes for Enhancing the Ocular Delivery of Acetazolamide: Statistical Optimization, In Vitro Characterization, and In Vivo Study. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050465"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/j.xphs.2019.01.016","article-title":"The Role of Surface Active Agents in Ophthalmic Drug Delivery: A Comprehensive Review","volume":"108","author":"Ibrahim","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"119402","DOI":"10.1016\/j.ijpharm.2020.119402","article-title":"Nanoemulsion as a feasible and biocompatible carrier for ocular delivery of travoprost: Improved pharmacokinetic\/pharmacodynamic properties","volume":"583","author":"Ismail","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105887","DOI":"10.1016\/j.ejps.2021.105887","article-title":"Gamma sterilization and in vivo evaluation of cationic nanostructured lipid carriers as potential ocular delivery systems for antiglaucoma drugs","volume":"163","author":"Youshia","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.jddst.2019.01.042","article-title":"Hyaluronic acid-coated solid lipid nanoparticles to overcome drug-resistance in tumor cells","volume":"50","author":"Lee","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Fern\u00e1ndez, F., Bianchera, A., Gasco, P., Nicoli, S., and Pescina, S. (2021). Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13040447"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1080\/1061186X.2020.1830408","article-title":"Improved oral delivery of quercetin with hyaluronic acid containing niosomes as a promising formulation","volume":"29","author":"Ebrahimnejad","year":"2021","journal-title":"J. Drug Target."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.carbpol.2017.12.015","article-title":"Synthesis and characterization of hyaluronic acid hydrogels crosslinked using a solvent-free process for potential biomedical applications","volume":"181","author":"Henry","year":"2018","journal-title":"Carbohydr. Polym."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.2147\/IJN.S104774","article-title":"Phytosome-hyaluronic acid systems for ocular delivery of L-carnosine","volume":"11","author":"Abdelkader","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"102026","DOI":"10.1016\/j.nano.2019.102026","article-title":"Development of Halobetasol-loaded nanostructured lipid carrier for dermal administration: Optimization, physicochemical and biopharmaceutical behavior, and therapeutic efficacy","volume":"20","author":"Espina","year":"2019","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.colsurfa.2017.04.010","article-title":"Zeta potential measurements for non-spherical colloidal particles \u2013 Practical issues of characterisation of interfacial properties of nanoparticles","volume":"532","author":"Babick","year":"2017","journal-title":"Colloids Surfaces A Physicochem. Eng. Asp."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"120051","DOI":"10.1016\/j.ijpharm.2020.120051","article-title":"Comprehensive analysis of liposome formulation parameters and their influence on encapsulation, stability and drug release in glibenclamide liposomes","volume":"592","author":"Maritim","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ijpharm.2016.02.039","article-title":"Biopharmaceutical evaluation of epigallocatechin gallate-loaded cationic lipid nanoparticles (EGCG-LNs): In vivo, in vitro and ex vivo studies","volume":"502","author":"Fangueiro","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105026","DOI":"10.1016\/j.ejps.2019.105026","article-title":"Interpreting non-linear drug diffusion data: Utilizing Korsmeyer-Peppas model to study drug release from liposomes","volume":"138","author":"Wu","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Romero, A.-M., Maestrelli, F., Mura, P.A., Rabasco, A.M., and Gonz\u00e1lez-Rodr\u00edguez, M.L. (2018). Novel Findings about Double-Loaded Curcumin-in-HP\u03b2cyclodextrin-in Liposomes: Effects on the Lipid Bilayer and Drug Release. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10040256"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Segura, L., Parra, A., Calpena-Campmany, A.C., Gimeno, \u00c1., De Aranda, I.G., and Boix-Monta\u00f1es, A. (2020). Ex Vivo Permeation of Carprofen Vehiculated by PLGA Nanoparticles through Porcine Mucous Membranes and Ophthalmic Tissues. Nanomaterials, 10.","DOI":"10.3390\/nano10020355"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Soni, V., Pandey, V., Tiwari, R., Asati, S., and Tekade, R.K. (2019). Design and Evaluation of Ophthalmic Delivery Formulations. Basic Fundamentals of Drug Delivery, Elsevier BV.","DOI":"10.1016\/B978-0-12-817909-3.00013-3"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.biochi.2008.07.007","article-title":"Role of lactoferrin in the tear film","volume":"91","author":"Flanagan","year":"2009","journal-title":"Biochimie"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Lawrenson, J.G. (2018). Anterior Eye. Contact Lens Practice, Elsevier.","DOI":"10.1016\/B978-0-7020-6660-3.00002-2"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1167\/iovs.61.12.9","article-title":"Lactoferrin Concentration in Human Tears and Ocular Diseases: A Meta-Analysis","volume":"61","author":"Ponzini","year":"2020","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fphar.2016.00185","article-title":"Bioerodable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading","volume":"7","author":"Han","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Li, Y., Ruan, S., Wang, Z., Feng, N., and Zhang, Y. (2021). Hyaluronic Acid Coating Reduces the Leakage of Melittin Encapsulated in Liposomes and Increases Targeted Delivery to Melanoma Cells. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081235"},{"key":"ref_73","first-page":"1","article-title":"Development of a novel hyaluronic acid membrane for the treatment of ocular surface diseases","volume":"11","author":"Kim","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.colsurfb.2018.11.065","article-title":"In-situ forming gels containing fluorometholone-loaded polymeric nanoparticles for ocular inflammatory conditions","volume":"175","author":"Bellowa","year":"2019","journal-title":"Colloids Surfaces B Biointerfaces"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Eldesouky, L., El-Moslemany, R., Ramadan, A., Morsi, M., and Khalafallah, N. (2021). Cyclosporine Lipid Nanocapsules as Thermoresponsive Gel for Dry Eye Management: Promising Corneal Mucoadhesion, Biodistribution and Preclinical Efficacy in Rabbits. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13030360"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejps.2017.01.013","article-title":"Studying the influence of formulation and process variables on Vancomycin-loaded polymeric nanoparticles as potential carrier for enhanced ophthalmic delivery","volume":"100","author":"Yousry","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Vagge, A., Senni, C., Bernabei, F., Pellegrini, M., Scorcia, V., E Traverso, C., and Giannaccare, G. (2020). Therapeutic Effects of Lactoferrin in Ocular Diseases: From Dry Eye Disease to Infections. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186668"},{"key":"ref_78","first-page":"NC06","article-title":"Effect of Oral Lactoferrin on Cataract Surgery Induced Dry Eye: A Randomised Controlled Trial","volume":"9","author":"Devendra","year":"2015","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7319","DOI":"10.1038\/s41598-019-43714-5","article-title":"Elevated cytokine levels in tears and saliva of patients with primary Sj\u00f6gren\u2019s syndrome correlate with clinical ocular and oral manifestations","volume":"9","author":"Chen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_80","first-page":"1","article-title":"Membrane vesicles from the probiotic Nissle 1917 and gut resident Escherichia coli strains distinctly modulate human dendritic cells and subsequent T cell responses","volume":"61","author":"Fabrega","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"150","DOI":"10.4103\/tjo.tjo_56_19","article-title":"Role of tear film biomarkers in the diagnosis and management of dry eye disease","volume":"9","author":"Shih","year":"2019","journal-title":"Taiwan J. Ophthalmol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/09273948.2016.1277247","article-title":"Roles of IL-6 in Ocular Inflammation: A Review","volume":"26","author":"Ghasemi","year":"2018","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.3389\/fimmu.2017.01438","article-title":"Lactoferrin in a Context of Inflammation-Induced Pathology","volume":"8","author":"Kruzel","year":"2017","journal-title":"Front. Immunol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/10\/1698\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:15:31Z","timestamp":1760166931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/10\/1698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,15]]},"references-count":83,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["pharmaceutics13101698"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13101698","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,15]]}}}