Low Acyl Gellan as an Excipient to Improve the Sprayability and Mucoadhesion of Iota Carrageenan in a Nasal Spray to Prevent Infection With SARS-CoV-2

DOI record: { "DOI": "10.3389/fmedt.2021.687681", "ISSN": [ "2673-3129" ], "URL": "http://dx.doi.org/10.3389/fmedt.2021.687681", "abstract": "<jats:p>The COVID-19 global pandemic, as well as the widespread persistence of influenza and the common cold, create the need for new medical devices such as nasal sprays to prevent viral infection and transmission. Carrageenan, a sulfated polysaccharide, has a broad, non-pharmacological antiviral capacity, however it performs poorly in two key areas; spray coverage and mucoadhesion. Therefore gellan, another polysaccharide, was investigated as an excipient to improve these properties. It was found that viscoelastic relaxation time was the key predictor of spray coverage, and by reducing this value from 2.5 to 0.25 s, a mix of gellan and carrageenan gave more than four times the coverage of carrageenan alone (<jats:italic>p</jats:italic> &amp;lt; 0.0001). Gellan also demonstrated enhanced adhesion to a mucus analog that increased significantly with time (<jats:italic>p</jats:italic> &amp;lt; 0.0001), suggesting the development of specific gellan–mucin interactions. This property was conferred to carrageenan on mixing the two polymers. Together, this data suggests that gellan is a promising excipient to improve both sprayability and mucoadhesion of carrageenan for use in antiviral nasal sprays.</jats:p>", "alternative-id": [ "10.3389/fmedt.2021.687681" ], "author": [ { "affiliation": [], "family": "Robinson", "given": "Thomas E.", "sequence": "first" }, { "affiliation": [], "family": "Moakes", "given": "Richard J. A.", "sequence": "additional" }, { "affiliation": [], "family": "Grover", "given": "Liam M.", "sequence": "additional" } ], "container-title": "Frontiers in Medical Technology", "container-title-short": "Front. Med. Technol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2021, 6, 16 ] ], "date-time": "2021-06-16T05:56:05Z", "timestamp": 1623822965000 }, "deposited": { "date-parts": [ [ 2021, 6, 16 ] ], "date-time": "2021-06-16T05:56:09Z", "timestamp": 1623822969000 }, "funder": [ { "DOI": "10.13039/100008081", "doi-asserted-by": "publisher", "name": "Dystrophic Epidermolysis Bullosa Research Association" } ], "indexed": { "date-parts": [ [ 2022, 12, 27 ] ], "date-time": "2022-12-27T05:55:36Z", "timestamp": 1672120536994 }, "is-referenced-by-count": 4, "issued": { "date-parts": [ [ 2021, 6, 16 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 6, 16 ] ], "date-time": "2021-06-16T00:00:00Z", "timestamp": 1623801600000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fmedt.2021.687681/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2021, 6, 16 ] ] }, "published-online": { "date-parts": [ [ 2021, 6, 16 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "key": "B1", "unstructured": "WHO Coronavirus (COVID-19) Dashboard. 12021" }, { "DOI": "10.1056/nejmoa032867", "article-title": "Evidence of airborne transmission of the severe acute respiratory syndrome virus", "author": "Yu", "doi-asserted-by": "publisher", "first-page": "1731", "journal-title": "N Engl J Med.", "key": "B2", "volume": "350", "year": "2004" }, { "DOI": "10.1073/pnas.1716561115", "article-title": "Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community", "author": "Yan", "doi-asserted-by": "publisher", "first-page": "1081", "journal-title": "Proc Natl Acad Sci USA.", "key": "B3", "volume": "115", "year": "2018" }, { "DOI": "10.1016/j.envint.2020.106112", "article-title": "Quantitative assessment of the risk of airborne transmission of SARS-CoV-2 infection: prospective and retrospective applications", "author": "Buonanno", "doi-asserted-by": "publisher", "first-page": "106112", "journal-title": "Environ. Int.", "key": "B4", "volume": "145", "year": "2020" }, { "DOI": "10.1101/2020.04.16.20067728", "article-title": "Evidence for probable aerosol transmission of SARS-CoV-2 in a poorly ventilated restaurant", "author": "Li", "doi-asserted-by": "publisher", "journal-title": "medRxiv.", "key": "B5", "year": "2020" }, { "DOI": "10.1111/ina.12751", "article-title": "Transmission of SARS-CoV-2 by inhalation of respiratory aerosol in the Skagit Valley Chorale superspreading event", "author": "Miller", "doi-asserted-by": "publisher", "first-page": "314", "journal-title": "Indoor Air.", "key": "B6", "volume": "31", "year": "2020" }, { "DOI": "10.1016/j.envint.2020.106039", "article-title": "Aerosol transmission of SARS-CoV-2? Evidence, prevention and control", "author": "Tang", "doi-asserted-by": "publisher", "first-page": "106039", "journal-title": "Environ Int.", "key": "B7", "volume": "144", "year": "2020" }, { "DOI": "10.1093/cid/ciaa939", "article-title": "It is time to address airborne transmission of coronavirus disease 2019 (COVID-19)", "author": "Morawska", "doi-asserted-by": "publisher", "first-page": "2311", "journal-title": "Clin Infect Dis.", "key": "B8", "volume": "71", "year": "2020" }, { "key": "B9", "unstructured": "SandovalM\n VergaraO\n Drops in the Wind: Their Dispersion and COVID-19 Implications" }, { "key": "B10", "unstructured": "ProctorDF\n Elsevier Biomed. PressThe Nose: Upper Airway Physiology and the Atmospheric Environment" }, { "DOI": "10.1097/00020840-199402000-00004", "article-title": "Nose and sinus airflow", "author": "Cole", "doi-asserted-by": "publisher", "first-page": "16", "journal-title": "Curr Opin Otolaryngol Head Neck Surg.", "key": "B11", "volume": "2", "year": "1994" }, { "DOI": "10.1177/194589240201600202", "article-title": "P. Wound healing of the nasal and paranasal mucosa: a review", "author": "Watelet", "doi-asserted-by": "publisher", "first-page": "77", "journal-title": "Am J Rhinol.", "key": "B12", "volume": "16", "year": "2002" }, { "DOI": "10.4103/2231-4040.90876", "article-title": "A review on mucoadhesive polymer used in nasal drug delivery system", "author": "Chaturvedi", "doi-asserted-by": "publisher", "first-page": "215", "journal-title": "J Adv Pharm Technol Res.", "key": "B13", "volume": "2", "year": "2011" }, { "DOI": "10.3390/ijms21020480", "article-title": "Current and alternative therapies for nasal mucosa injury: a review", "author": "Selvarajah", "doi-asserted-by": "publisher", "first-page": "480", "journal-title": "Int J Mol Sci.", "key": "B14", "volume": "21", "year": "2020" }, { "DOI": "10.1080/14789450.2020.1748502", "article-title": "Nasal mucus proteome and its involvement in allergic rhinitis", "author": "Tomazic", "doi-asserted-by": "publisher", "first-page": "191", "journal-title": "Expert Rev Proteomics.", "key": "B15", "volume": "17", "year": "2020" }, { "DOI": "10.1165/rcmb.2005-0436SF", "article-title": "Airway mucus: from production to secretion", "author": "Williams", "doi-asserted-by": "publisher", "first-page": "527", "journal-title": "Am J Respir Cell Mol Biol.", "key": "B16", "volume": "34", "year": "2006" }, { "article-title": "Physiology of airway mucus secretion and pathophysiology of hypersecretion", "author": "Roger", "first-page": "1134", "journal-title": "Respir Care", "key": "B17", "year": "2007" }, { "DOI": "10.1080/10837450.2020.1753771", "article-title": "Mucoadhesive formulations: innovations, merits, drawbacks, future outlook", "author": "Kumar", "doi-asserted-by": "publisher", "first-page": "797", "journal-title": "Pharm Dev Technol.", "key": "B18", "volume": "25", "year": "2020" }, { "DOI": "10.4103/0975-7406.76478", "article-title": "Mucoadhesive drug delivery systems", "author": "Shaikh", "doi-asserted-by": "publisher", "first-page": "89", "journal-title": "J Pharm Bioallied Sci.", "key": "B19", "volume": "3", "year": "2011" }, { "DOI": "10.5138/ijdd.v3i2.214", "article-title": "A review on factors affecting the design of nasal drug delivery system", "author": "Dhakar", "doi-asserted-by": "publisher", "first-page": "29", "journal-title": "Int J Drug Deliv.", "key": "B20", "volume": "3", "year": "" }, { "DOI": "10.2174/156720112803529828", "article-title": "Anatomical and histological factors affecting intranasal drug and vaccine delivery", "author": "Gizurarson", "doi-asserted-by": "publisher", "first-page": "566", "journal-title": "Curr Drug Deliv.", "key": "B21", "volume": "9", "year": "2012" }, { "DOI": "10.1038/s41591-020-0868-6", "article-title": "SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes", "author": "Sungnak", "doi-asserted-by": "publisher", "first-page": "681", "journal-title": "Nat Med.", "key": "B22", "volume": "26", "year": "2020" }, { "DOI": "10.1016/j.bbrc.2020.07.029", "article-title": "Acidic electrolyzed water potently inactivates SARS-CoV-2 depending on the amount of free available chlorine contacting with the virus", "author": "Takeda", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Biochem Biophys Res Commun.", "key": "B23", "volume": "530", "year": "2020" }, { "DOI": "10.1101/2020.11.04.361154", "article-title": "Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets", "author": "de Vries", "doi-asserted-by": "publisher", "first-page": "1379", "journal-title": "Science.", "key": "B24", "volume": "371", "year": "2021" }, { "DOI": "10.26717/BJSTR.2021.33.005405", "article-title": "TaffiX® nasal powder forms an effective barrier against SARS-CoV-2", "author": "Mann", "doi-asserted-by": "publisher", "first-page": "25843", "journal-title": "Biomed J Sci Tech Res.", "key": "B25", "volume": "33", "year": "2021" }, { "DOI": "10.1101/2020.11.18.388645", "article-title": "Formulation of a composite nasal spray enabling enhanced surface coverage and prophylaxis of SARS-COV-2", "author": "Moakes", "doi-asserted-by": "publisher", "journal-title": "bioRxiv", "key": "B26", "year": "2020" }, { "DOI": "10.1016/j.ijbiomac.2016.11.095", "article-title": "A review on synthesis, properties and applications of natural polymer based carrageenan blends and composites", "author": "Zia", "doi-asserted-by": "publisher", "first-page": "282", "journal-title": "Int J Biol Macromol.", "key": "B27", "volume": "96", "year": "2017" }, { "DOI": "10.1186/1465-9921-11-108", "article-title": "Efficacy and safety of an antiviral iota-carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold", "author": "Eccles", "doi-asserted-by": "publisher", "first-page": "108", "journal-title": "Respir Res.", "key": "B28", "volume": "11", "year": "2010" }, { "DOI": "10.1186/2049-6958-9-57", "article-title": "Carrageenan nasal spray in virus confirmed common cold: individual patient data analysis of two randomized controlled trials", "author": "Koenighofer", "doi-asserted-by": "publisher", "first-page": "57", "journal-title": "Multidiscip Respir Med.", "key": "B29", "volume": "9", "year": "2014" }, { "DOI": "10.2174/1874357902014010009", "article-title": "Iota-carrageenan as an antiviral treatment for the common cold", "author": "Eccles", "doi-asserted-by": "publisher", "first-page": "9", "journal-title": "Open Virol J.", "key": "B30", "volume": "14", "year": "2020" }, { "DOI": "10.1371/journal.pone.0014320", "article-title": "Iota-carrageenan is a potent inhibitor of influenza a virus infection", "author": "Leibbrandt", "doi-asserted-by": "publisher", "first-page": "e14320", "journal-title": "PLoS ONE.", "key": "B31", "volume": "5", "year": "2010" }, { "DOI": "10.1038/s41598-020-80896-9", "article-title": "Antiviral activity of lambda-carrageenan against influenza viruses and severe acute respiratory syndrome coronavirus 2", "author": "Jang", "doi-asserted-by": "publisher", "first-page": "821", "journal-title": "Sci Rep.", "key": "B32", "volume": "11", "year": "2021" }, { "DOI": "10.1007/s10811-020-02143-y", "article-title": "The COVID 19 novel coronavirus pandemic 2020: seaweeds to the rescue? Why does substantial, supporting research about the antiviral properties of seaweed polysaccharides seem to go unrecognized by the pharmaceutical community in these desperate times?", "author": "Pereira", "doi-asserted-by": "publisher", "first-page": "1875", "journal-title": "J Appl Phycol.", "key": "B33", "volume": "32", "year": "2020" }, { "DOI": "10.1371/journal.pone.0237480", "article-title": "Iota-carrageenan neutralizes SARS-CoV-2 and inhibits viral replication in vitro", "author": "Morokutti-Kurz", "doi-asserted-by": "publisher", "first-page": "e0237480", "journal-title": "PLoS ONE.", "key": "B34", "volume": "16", "year": "2021" }, { "DOI": "10.1016/j.cemconres.2004.02.020", "article-title": "Estimating rheological properties of cement pastes using various rheological models for different test geometry, gap and surface friction", "author": "Nehdi", "doi-asserted-by": "publisher", "first-page": "1993", "journal-title": "Cem Concr Res.", "key": "B35", "volume": "34", "year": "2004" }, { "DOI": "10.5334/jors.97", "article-title": "Pendent_Drop: an imagej plugin to measure the surface tension from an image of a pendent drop", "author": "Daerr", "doi-asserted-by": "publisher", "first-page": "3", "journal-title": "J Open Res Softw.", "key": "B36", "volume": "4", "year": "2016" }, { "DOI": "10.1016/j.colsurfa.2006.03.008", "article-title": "A snake-based approach to accurate determination of both contact points and contact angles", "author": "Stalder", "doi-asserted-by": "publisher", "first-page": "92", "journal-title": "Coll Surf A Physicochem Eng Asp.", "key": "B37", "volume": "286", "year": "2006" }, { "DOI": "10.1016/j.colsurfa.2010.04.040", "article-title": "Low-bond axisymmetric drop shape analysis for surface tension and contact angle measurements of sessile drops", "author": "Stalder", "doi-asserted-by": "publisher", "first-page": "72", "journal-title": "Coll Surf A Physicochem Eng Asp.", "key": "B38", "volume": "364", "year": "2010" }, { "DOI": "10.1186/1472-6882-12-147", "article-title": "Lessons learned from a double-blind randomised placebo-controlled study with a iota-carrageenan nasal spray as medical device in children with acute symptoms of common cold", "author": "Fazekas", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "BMC Complement Altern Med.", "key": "B39", "volume": "12", "year": "2012" }, { "DOI": "10.1186/1465-9921-14-124", "article-title": "Efficacy of a carrageenan nasal spray in patients with common cold: a randomized controlled trial", "author": "Ludwig", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Respir Res.", "key": "B40", "volume": "14", "year": "2013" }, { "DOI": "10.2147/IJGM.S167123", "article-title": "Development of a nasal spray containing xylometazoline hydrochloride and iota-carrageenan for the symptomatic relief of nasal congestion caused by rhinitis and sinusitis", "author": "Graf", "doi-asserted-by": "publisher", "first-page": "275", "journal-title": "Int J Gen Med.", "key": "B41", "volume": "11", "year": "2018" }, { "DOI": "10.1007/s10811-017-1132-4", "article-title": "The carrageenan controversy", "author": "Bixler", "doi-asserted-by": "publisher", "first-page": "2201", "journal-title": "J Appl Phycol", "key": "B42", "year": "2017" }, { "DOI": "10.2903/j.efsa.2018.5296", "article-title": "Re-evaluation of gellan gum (E 418) as food additive", "author": "Younes", "doi-asserted-by": "publisher", "first-page": "5296", "journal-title": "EFSA J.", "key": "B43", "volume": "16", "year": "2018" }, { "key": "B44", "unstructured": "Gellan gum85585\n SwornG\n StoubyL\n \n PhillipsGO\n WilliamsPA\n CambridgeWoodhead Publishing LtdHandbook of Hydrocolloids.2021" }, { "DOI": "10.1002/ppsc.19890060129", "article-title": "Properties of sprays", "author": "Lefebvre", "doi-asserted-by": "publisher", "first-page": "176", "journal-title": "Part Part Syst Charact.", "key": "B45", "volume": "6", "year": "1989" }, { "DOI": "10.1016/j.applthermaleng.2017.04.089", "article-title": "Spray characteristics of pressure-swirl nozzles at different nozzle diameters", "author": "Zhang", "doi-asserted-by": "publisher", "first-page": "984", "journal-title": "Appl Therm Eng.", "key": "B46", "volume": "121", "year": "2017" }, { "DOI": "10.3390/en13236309", "article-title": "Effect of rheological properties of aqueous solution of na-cmc on spray angle for conical pressure-swirl atomizers", "author": "Czernek", "doi-asserted-by": "publisher", "first-page": "6309", "journal-title": "Energies.", "key": "B47", "volume": "13", "year": "2020" }, { "DOI": "10.1103/PhysRevX.8.031019", "article-title": "What determines the drop size in sprays?", "author": "Kooij", "doi-asserted-by": "publisher", "first-page": "31019", "journal-title": "Phys Rev X.", "key": "B48", "volume": "8", "year": "2018" }, { "DOI": "10.1002/ps.5742", "article-title": "The effect of adjuvants on spray droplet size from hydraulic nozzles", "author": "Sijs", "doi-asserted-by": "publisher", "first-page": "3487", "journal-title": "Pest Manag Sci.", "key": "B49", "volume": "76", "year": "2020" }, { "DOI": "10.1016/S0141-8130(00)00141-0", "article-title": "Viscoelastic properties for kappa- and iota-carrageenan in aqueous NaI from the liquid-like to the solid-like behaviour", "author": "Chronakis", "doi-asserted-by": "publisher", "first-page": "1", "journal-title": "Int J Biol Macromol.", "key": "B50", "volume": "28", "year": "2000" }, { "DOI": "10.1021/bm901063k", "article-title": "Viscoelasticity and phase separation of aqueous Na-type gellan solution", "author": "Nitta", "doi-asserted-by": "publisher", "first-page": "187", "journal-title": "Biomacromolecules.", "key": "B51", "volume": "11", "year": "2010" }, { "DOI": "10.1016/0377-0257(94)85031-3", "article-title": "Rheological characterization of the time and strain dependence for polyisobutylene solutions", "author": "Liang", "doi-asserted-by": "publisher", "first-page": "387", "journal-title": "J Nonnewton Fluid Mech.", "key": "B52", "volume": "52", "year": "1994" }, { "DOI": "10.1021/ma00122a041", "article-title": "Dynamic viscoelastic modulus of associative polymer networks: off-lattice simulations, theory and comparison to experiments", "author": "Groot", "doi-asserted-by": "publisher", "first-page": "6284", "journal-title": "Macromolecules.", "key": "B53", "volume": "28", "year": "1995" }, { "DOI": "10.1016/S0268-005X(96)80002-6", "article-title": "Characterization and properties of gellan-κ-carrageenan mixed gels", "author": "Nishinari", "doi-asserted-by": "publisher", "first-page": "277", "journal-title": "Food Hydrocoll.", "key": "B54", "volume": "10", "year": "1996" }, { "DOI": "10.1016/S0268-005X(98)00070-8", "article-title": "Dynamic viscoelastic behavior of gellan- ι -carrageenan and gellan-xanthan gels", "author": "Rodríguez-Hernández", "doi-asserted-by": "publisher", "first-page": "59", "journal-title": "Food Hydrocoll.", "key": "B55", "volume": "13", "year": "1999" }, { "DOI": "10.1016/j.carbpol.2008.07.037", "article-title": "Viscosity study of interactions between sodium alginate and CTAB in dilute solutions at different pH values", "author": "Yang", "doi-asserted-by": "publisher", "first-page": "333", "journal-title": "Carbohydr Polym.", "key": "B56", "volume": "75", "year": "2009" }, { "DOI": "10.1016/J.POLYMER.2011.03.053", "article-title": "Increasing viscosity in entangled polyelectrolyte solutions by the addition of salt", "author": "Wyatt", "doi-asserted-by": "publisher", "first-page": "2437", "journal-title": "Polymer (Guildf).", "key": "B57", "volume": "52", "year": "2011" }, { "DOI": "10.1016/j.mtbio.2020.100059", "article-title": "Local injection of a hexametaphosphate formulation reduces heterotopic ossification in vivo", "author": "Robinson", "doi-asserted-by": "publisher", "first-page": "100059", "journal-title": "Mater Today Bio", "key": "B58", "volume": "7", "year": "2020" }, { "DOI": "10.1002/adhm.201901521", "article-title": "Filling the gap: a correlation between objective and subjective measures of injectability", "author": "Robinson", "doi-asserted-by": "publisher", "first-page": "1901521", "journal-title": "Adv Healthc Mater.", "key": "B59", "volume": "9", "year": "2020" }, { "DOI": "10.1002/mabi.201000388", "article-title": "Advances in mucoadhesion and mucoadhesive polymers", "author": "Khutoryanskiy", "doi-asserted-by": "publisher", "first-page": "748", "journal-title": "Macromol Biosci.", "key": "B60", "volume": "11", "year": "2011" }, { "DOI": "10.1016/j.ejpb.2013.06.023", "article-title": "Assessment of test methods evaluating mucoadhesive polymers and dosage forms: an overview", "author": "Woertz", "doi-asserted-by": "publisher", "first-page": "843", "journal-title": "Eur J Pharm Biopharm.", "key": "B61", "volume": "85", "year": "2013" }, { "DOI": "10.1163/092764409X12477478334847", "article-title": "Relationship between interfacial adhesion and viscosity of cellulose fiber filled polypropylene and poly(ε-caprolactone): a review", "author": "Kim", "doi-asserted-by": "publisher", "first-page": "583", "journal-title": "Compos Interfaces.", "key": "B62", "volume": "16", "year": "2009" }, { "DOI": "10.1016/j.ijpharm.2015.04.011", "article-title": "Development of mucoadhesive sprayable gellan gum fluid gels", "author": "Mahdi", "doi-asserted-by": "publisher", "first-page": "12", "journal-title": "Int J Pharm.", "key": "B63", "volume": "488", "year": "2015" }, { "DOI": "10.1016/j.ijbiomac.2020.01.235", "article-title": "Mucin-polysaccharide interactions: a rheological approach to evaluate the effect of pH on the mucoadhesive properties", "author": "de Oliveira Cardoso", "doi-asserted-by": "publisher", "first-page": "234", "journal-title": "Int J Biol Macromol.", "key": "B64", "volume": "149", "year": "2020" } ], "reference-count": 64, "references-count": 64, "relation": {}, "resource": { "primary": { "URL": 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