{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T21:37:15Z","timestamp":1778189835820,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nisin, a food preservative lantibiotic produced by Lactococcus lactis, exhibits potent antimicrobial activity against a wide range of Gram-positive pathogens, including antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). This study explores the development of a novel nano drug delivery platform comprising nisin-loaded niosomes, formulated via microfluidic mixing, and integrated into fast-dissolving oral films for targeted buccal administration. Microfluidic synthesis enabled the precise control of critical parameters including the flow rate ratio, surfactant composition, and lipid concentration, resulting in uniform niosomal vesicles with optimal size distribution (100\u2013200 nm), low polydispersity index, and high encapsulation efficiency. Span 40 and Span 60 were employed as non-ionic surfactants, stabilized with cholesterol to improve bilayer rigidity and drug retention. The encapsulated nisin demonstrated improved physicochemical stability over time and protection against proteolytic degradation, thus preserving its antimicrobial potency. The niosomal suspensions were subsequently incorporated into polymer-based oral films as a final dosage form composed of polyvinyl alcohol (PVA) as the primary film-forming polymer, polyethylene glycol 400 (PEG400) as a plasticizer, and sucralose and mint as a sweetener and flavoring agent, respectively. A disintegrant was added to accelerate film dissolution in the oral cavity, facilitating the rapid release of niosomal nisin. The films were cast and evaluated for thickness uniformity, mechanical properties, disintegration time, surface morphology, and drug content uniformity. The dried films exhibited desirable flexibility, rapid disintegration (&lt;30 s), and consistent distribution of nisin-loaded vesicles. In vitro antimicrobial assays confirmed that the bioactivity of nisin was retained post-formulation, showing effective inhibition zones (16 mm) against Bacillus subtilis. This delivery system offers a promising platform for localized antimicrobial therapy in the oral cavity, potentially aiding in the treatment of dental plaque, oral infections, and periodontal diseases. Overall, the integration of microfluidic-synthesized nisin niosomes into oral films presents a novel, non-invasive strategy for enhancing the stability and therapeutic efficacy of peptide-based drugs in mucosal environments. Physicochemical characterization of the niosomes and niosome films was performed using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to evaluate thermal stability and scanning electron microscopy (SEM) to assess surface morphology. In vitro peptide release studies demonstrated sustained release from both niosomal suspensions and film matrices, and the resulting data were further fitted to established kinetic models to elucidate the underlying drug release mechanisms. This delivery system offers a promising platform for localized antimicrobial therapy in the oral cavity, potentially aiding in the treatment of dental plaque, oral infections, and periodontal diseases. Overall, the integration of microfluidic-synthesized nisin niosomes into oral films presents a novel, non-invasive strategy for enhancing the stability and therapeutic efficacy of peptide-based drugs in mucosal environments.<\/jats:p>","DOI":"10.3390\/molecules30183715","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:08:16Z","timestamp":1757678896000},"page":"3715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fast-Disintegrating Oral Films Containing Nisin-Loaded Niosomes"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1780-2187","authenticated-orcid":false,"given":"Ali A.","family":"Amer","sequence":"first","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4855-2635","authenticated-orcid":false,"given":"Yasir","family":"Karkar","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lewis","family":"Bingle","sequence":"additional","affiliation":[{"name":"School of Nursing and Health Sciences, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0781-1127","authenticated-orcid":false,"given":"Amal Ali","family":"Elkordy","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7450-4100","authenticated-orcid":false,"given":"Cheng Shu","family":"Chaw","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33265","DOI":"10.1021\/acsomega.1c05083","article-title":"Nanoarchitectonics of Multifunctional Niosomes for Advanced Drug De-livery","volume":"6","author":"Momekova","year":"2021","journal-title":"ACS Omega"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.1021\/ja00747a073","article-title":"Structure of nisin","volume":"93","author":"Gross","year":"1971","journal-title":"J. Am. Chem. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10329","DOI":"10.1039\/C9RA10135G","article-title":"Nisin\/polyanion layer-by-layer films exhibiting different mechanisms in antimicrobial efficacy","volume":"10","author":"Fael","year":"2020","journal-title":"RSC Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1128\/aem.56.8.2551-2558.1990","article-title":"Some chemical and physical properties of nisin, a small-protein antibiotic produced by Lactococcus lactis","volume":"56","author":"Liu","year":"1990","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF00399424","article-title":"Applications of the bacteriocin, nisin","volume":"69","author":"Blackburn","year":"1996","journal-title":"Antonie Van Leeuwenhoek"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/j.1432-1033.1991.tb16317.x","article-title":"Identification and characterization of the lantibiotic nisin Z, a natural nisin variant","volume":"201","author":"Mulders","year":"1991","journal-title":"Eur. J. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/nsmb830","article-title":"The nisin\u2013lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics","volume":"11","author":"Hsu","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_8","first-page":"47","article-title":"Nisin: Production and mechanism of antimicrobial action","volume":"7","author":"Phumkhachorn","year":"2015","journal-title":"Int. J. Curr. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.2174\/1872215611307010010","article-title":"Recent Patents on Bacteriocins: Food and Biomedical Applications","volume":"7","author":"Benmechernene","year":"2013","journal-title":"Recent Pat. DNA Gene Seq."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1093\/jac\/dkp221","article-title":"A comparison of the activities of lacticin 3147 and nisin against drug-resistant Staphylococcus aureus and Enterococcus species","volume":"64","author":"Piper","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.micron.2007.06.013","article-title":"Microscopical investigations of nisin-loaded nanoliposomes prepared by Mozafari method and their bacterial targeting","volume":"38","author":"Colas","year":"2007","journal-title":"Micron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1111\/jam.13033","article-title":"Biomedical applications of nisin","volume":"120","author":"Shin","year":"2015","journal-title":"J. Appl. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.1128\/AAC.00888-13","article-title":"Effects of Bacteriocins on Methicillin-Resistant Staphylococcus aureus Biofilm","volume":"57","author":"Okuda","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1365-2672.1978.tb04203.x","article-title":"The Effects of Nisin on the Microbial Flora of the Dental Plaque of Monkeys (Macaca fascicularis)","volume":"45","author":"Johnson","year":"1978","journal-title":"J. Appl. Bacteriol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1600-051X.1993.tb00369.x","article-title":"The effect of a mouthrinse based on nisin, a bacteriocin, on developing plaque and gingivitis in beagle dogs","volume":"20","author":"Howell","year":"1993","journal-title":"J. Clin. Periodontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ijpharm.2015.02.063","article-title":"Microfluidic-controlled manufacture of liposomes for the solubilisation of a poorly water soluble drug","volume":"485","author":"Kastner","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2015.03.006","article-title":"Oral films: Current status and future perspectives","volume":"206","author":"Borges","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Amer, A.A., Bingle, L., Chaw, C.S., and Elkordy, A.A. (2025). Development of Vancomycin, a Glycopeptide Antibiotic, in a Suitable Nanoform for Oral Delivery. Molecules, 30.","DOI":"10.3390\/molecules30071624"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rulence, A., Perreault, V., Thibodeau, J., Firdaous, L., Fliss, I., and Bazinet, L. (2023). Nisin Purification from a Cell-Free Supernatant by Electrodialysis in a Circular Economy Framework. Membranes, 14.","DOI":"10.3390\/membranes14010002"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Field, D., Cotter, P.D., Hill, C., and Ross, R.P. (2015). Bioengineering Lantibiotics for Therapeutic Success. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.01363"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.1007\/s10570-018-2010-1","article-title":"Bacterial nanocellulose membranes combined with nisin: A strategy to prevent microbial growth","volume":"25","author":"Soeiro","year":"2018","journal-title":"Cellulose"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chung, H.-S., and Lee, M. (2022). Different Antimicrobial Susceptibility Testing Methods to Determine Vancomycin Susceptibility and MIC for Staphylococcus aureus with Reduced Vancomycin Susceptibility. Diagnostics, 12.","DOI":"10.3390\/diagnostics12040845"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jeong, J.-P., Yoon, I., Kim, K., and Jung, S. (2024). Structural and Physiochemical Properties of Polyvinyl Alcohol\u2013Succinoglycan Biodegradable Films. Polymers, 16.","DOI":"10.3390\/polym16131783"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Borrmann, D., Danzer, A., and Sadowski, G. (2022). Water Sorption in Glassy Polyvinylpyrrolidone-Based Polymers. Membranes, 12.","DOI":"10.3390\/membranes12040434"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/S0142-9612(00)00046-6","article-title":"Physical\u2013mechanical, moisture absorption and bioadhesive properties of hydroxypropylcellulose hot-melt extruded films","volume":"21","author":"Repka","year":"2000","journal-title":"Biomaterials"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Panraksa, P., Tipduangta, P., Jantanasakulwong, K., and Jantrawut, P. (2020). Formulation of Orally Disintegrating Films as an Amorphous Solid Solution of a Poorly Water-Soluble Drug. Membranes, 10.","DOI":"10.3390\/membranes10120376"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.carbpol.2018.12.021","article-title":"Design and optimization of process parameters of polyvinyl (alcohol)\/chitosan\/nano zinc oxide hydrogels as wound healing materials","volume":"207","author":"Khorasani","year":"2019","journal-title":"Carbohydr. Polym."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1021\/acsomega.2c05110","article-title":"Physicochemical Characteristics and Antibacterial Activities of Freeze-Thawed Polyvinyl Alcohol\/Andrographolide Hydrogels","volume":"8","author":"Luthfianti","year":"2023","journal-title":"ACS Omega"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tsioptsias, C., Fardis, D., Ntampou, X., Tsivintzelis, I., and Panayiotou, C. (2023). Thermal Behavior of Poly(vinyl alcohol) in the Form of Physically Crosslinked Film. Polymers, 15.","DOI":"10.3390\/polym15081843"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.2174\/0115672018261294231024093926","article-title":"Development of Polyvinyl Alcohol\/Polyethylene Glycol Copolymer-based Orodispersible Films Loaded with Entecavir: Formulation and In vitro Characterization","volume":"21","author":"Wei","year":"2024","journal-title":"Curr. Drug Deliv."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Karkar, Y., Anis, T., Elkordy, A.A., and Faheem, A. (2025). Flexipill: A novel 3D printed flexible dose combination for hypertension with a floating element. Eur. J. Pharm. Biopharm., 212.","DOI":"10.1016\/j.ejpb.2025.114736"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/18\/3715\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:44:35Z","timestamp":1760035475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/18\/3715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":31,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["molecules30183715"],"URL":"https:\/\/doi.org\/10.3390\/molecules30183715","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]}}}