WO2014147287A1 - Cellulose nanocristalline (ncc) en tant que composé antiviral - Google Patents

Cellulose nanocristalline (ncc) en tant que composé antiviral Download PDF

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WO2014147287A1
WO2014147287A1 PCT/FI2013/050979 FI2013050979W WO2014147287A1 WO 2014147287 A1 WO2014147287 A1 WO 2014147287A1 FI 2013050979 W FI2013050979 W FI 2013050979W WO 2014147287 A1 WO2014147287 A1 WO 2014147287A1
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ncc
antiviral
groups
cellulose
nanoparticles
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PCT/FI2013/050979
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Jukka Seppälä
Justin ZOPPE
Kristiina JÄRVINEN
Ari Hinkkanen
Ville RUOTTINEN
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Jukka Seppälä
Zoppe Justin
Järvinen Kristiina
Ari Hinkkanen
Ruottinen Ville
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Publication of WO2014147287A1 publication Critical patent/WO2014147287A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/08—Fractionation of cellulose, e.g. separation of cellulose crystallites
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N65/00—Biocides, pest repellants or attractants, or plant growth regulators containing material from algae, lichens, bryophyta, multi-cellular fungi or plants, or extracts thereof
    • A01N65/08—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B5/00—Preparation of cellulose esters of inorganic acids, e.g. phosphates
    • C08B5/14—Cellulose sulfate

Definitions

  • NCC NANOCRYSTALLINE CELLULOSE
  • the present invention relates to nanocrystalline cellulose (NCC) as an anti-viral compound.
  • NCC nanocrystalline cellulose
  • the invention also relates to a process for producing NCC, and the use of NCC for reducing the risk of viral infections, or for treating or preventing viral infections.
  • the invention relates to a composition of such NCC, for reducing the risk of transmission, or treating or preventing viral infections; to a process for producing such a composition; and the use of such a composition.
  • HIV human immunodeficiency virus
  • One family of inhibitors are based on polyanionic compounds which prevent virus binding to target cells via electrostatic interactions with the viral envelope [Pirrone, V. et al., Antiviral Res. 2011, 90, 168- 182].
  • polystyrene sulfonate and polysaccharides, such as cellulose sulfate and cellulose acetate phthalate, which have a long history of antiviral activity.
  • polystyrene sulfonate and polysaccharides, such as cellulose sulfate and cellulose acetate phthalate, which have a long history of antiviral activity.
  • polyanionic compounds are effective against many viruses in vitro, such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), influenza and human papillomavirus (HPV).
  • HCV human immunodeficiency virus
  • HSV herpes simplex virus
  • HPV human papillomavirus
  • Polysulfated compounds were cautioned against systemic administration due to interference with blood coagulation [Flexner, C. et al., Antimicrob Agents
  • Anionic acid groups in proteins have a critical role in binding events of biological systems; for example, they facilitate the HIV-1 virus entry into host T-cells and macrophages [Stone, M. J. et al., New Biotechnol. 2009, 25, 299].
  • Systems that successfully mimic these interactions for HIV inhibition include nanoparticles with sulfate groups [Di Gianvincenzo, P. et al., Bioorg. Med. Chem. Lett. 2010, 20, 2718] and drug-like small molecules containing phenyl sulfonate groups [Acharya, P. et al., ACS Chem. Biol.
  • Powdered forms of cellulose have a long history of use in the pharmaceutical industry. Powdered cellulose is used as an excipient in various dosage forms, including tablets, two-piece hard capsules, soft capsules, aqueous suspensions for per oral delivery and suppositories [Rowe, R. C. et al. (editors), Handbook of Pharmaceutical Excipients, Pharmaceutical Press and American Pharmacists Association, 2012]. Typically, the form of cellulose that is termed microcrystalline cellulose (MCC) is used in tablets. MCC is purified, depolymerized alpha-cellulose derived from plant sources [O'Connor, R. E. et al., Pharm. Res. 1993, 10, 356-61]. MCC is generally recognized as safe (GRAS) by the US Food & Drug
  • Nanocrystalline cellulose is extracted from cellulosic biomass by acid hydrolytic extraction processes.
  • Nanocrystalline cellulose also known as cellulose nanocrystals (CNCs) or cellulose whiskers, have a very high surface area to volume ratio due to the nanometer size of the rod-shaped crystals.
  • NCC is non-cytotoxic [Lam, E. et al., Trends Biotechnol. 2012, 30, 283-290, Jackson, J. K. et al., Int. J. Nanomed. 2011, 6, 321-330 and Dong, S.
  • NCC nano LIFE 2012, 2, 1241006
  • NCC nano LIFE 2012, 2, 1241006
  • US 8309708 B2 concerns crystalline sulfated cellulose II and its production.
  • Crystalline sulfated cellulose II referred to in this patent is derived from the acid soluble polysaccharides (residual stream) after sulfuric acid hydrolysis of native cellulose I.
  • the said sulfated cellulose II is regenerated from solubilized fractions and has a molecular weight ⁇ 10,000 g/mol.
  • the acid insoluble rod-shaped nanocrystalline cellulose (NCC) is in the native cellulose I form with molecular weight of >15,000 g/mol.
  • NCC the surface of NCC, rod-shaped nanoparticles, is derivatized with sulfate groups.
  • cellulose-based anionic polymers which are cellulose derivatives with 32-35 wt.% substitution.
  • the starting materials utilized for synthesis of cellulose-based anionic polymers are commercially available cellulose derivatives such as cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT) and hydroxypropyl methyl cellulose phthalate (HPMCP).
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • HPPMCP hydroxypropyl methyl cellulose phthalate
  • sulfation or sulfonation of cellulose derivatives is achieved with either sulfur trioxide or anhydride chemistries of individual cellulose polymer chains.
  • nanocrystalline cellulose rod- shaped nanoparticles
  • NCC nanocrystalline cellulose
  • a number of native cellulosic raw materials such as cotton fibers or filter paper, which results in an overall degree of sulfation from 2-7 wt.%.
  • NCC can be desulfated and optionally further derivatized using e.g. epoxide and isothiocyanate chemistries.
  • the derivatization of NCC with sulfate and phenyl sulfonate groups only occurs on the surface of the rod-shaped nanoparticles.
  • US 20090247740 A1 describes spherical sulfated cellulose particles above 50 micron in size, such that they are not on the nano scale.
  • spherical sulfated cellulose is produced by sulfuric anhydride esterification.
  • rod-shaped nanoparticles ⁇ 1 micron termed nanocrystalline cellulose (NCC) are derived purely from sulfuric acid hydrolysis.
  • JP 2008266265A describes sulfated cellulose, where individual cellulose polymer chains which have been sulfate esterified at least 12% wt, which can be termed cellulose sulfate.
  • rod-shaped nanoparticles ⁇ 1 micron of NCC produced from sulfuric acid hydrolysis are only derivatized with sulfate groups on the surface (2-7 wt. %).
  • EP 2040716 B1 also describes sulfated cellulose for treatment of Rhinovirus infection, where individual cellulose polymer chains which have been sulfate esterified at least 12% wt., which can be termed cellulose sulfate.
  • rod- shaped nanoparticles, ⁇ 1 micron, of NCC produced from sulfuric acid hydrolysis are only derivatized with sulfate groups on the surface (2-7% wt.).
  • US 7235536 B2 describes sulfated cellulose for treatment of papilloma virus infection.
  • individual cellulose polymer chains which have been sulfate esterified at least 12% wt., which can be termed cellulose sulfate and has a molecular weight >500,000 g/mol.
  • rod-shaped nanoparticles, ⁇ 1 micron, of NCC produced from sulfuric acid hydrolysis are only derivatized with sulfate groups on the surface (2-7% wt).
  • WO 2005004882 A1 describes antiviral charged polymers. The sulfated
  • polysaccharides are carboxymethyl dextran sulfate or carboxymethyl cellulose that has been sulfate esterifed, preferably at least 13% wt. This refers to individual carboxymethyl cellulose polymer chains that have been derivatized with anionic groups.
  • rod-shaped nanoparticles, ⁇ 1 micron, of NCC produced from sulfuric acid hydrolysis are only derivatized with sulfate groups on the surface (2-7 wt. %).
  • NCC that exhibits anti-viral properties typically bears hydroxyl groups and/or anionic acid groups, such as sulfate, sulfonate, phenyl sulfate, or phenyl sulfonate groups, on the crystal surfaces.
  • NCC is capable of inhibiting infection by fluorescent Semliki Forest virus (SFV) vector VA7-EGFP and parental SFV rA774 virus of primate cells in vitro the magnitude of inhibition being dependent on NCC concentration and surface functionality (see Figure 1 and 3).
  • SFV fluorescent Semliki Forest virus
  • HCE human corneal epithelial
  • Vero B African green monkey kidney
  • Semliki Forest Virus (SFV), closely related to the Chikungunya Virus (CHIK), is an arthropod-borne alphavirus found in parts of Africa and is known to cause disease in domestic animals and humans [Gibbons, D. L. et al., Nature (London, U. K.) 2004, 427, 320-325, Helenius, A. et al., J. Cell Biol. 1980, 84, 404-20, Lescar, J. et al., Cell (Cambridge, MA, U. S.) 2001, 105, 137-148 and Strauss, J. H. et al., Microbiol. Rev. 1994, 58, 491-562].
  • This invention seeks to provide nanocrystalline cellulose (NCC) for reducing the risk of viral infections, or for treating or preventing of viral infections.
  • NCC nanocrystalline cellulose
  • Such NCC typically bears hydroxyl groups and/or anionic acid groups, such as sulfate, sulfonate, phenyl sulfate, or phenyl sulfonate groups, on the crystal surfaces.
  • This invention also seeks to provide a composition comprising an effective amount of nanocrystalline cellulose (NCC) for reducing risk of viral infections, or for treating or preventing of viral infections.
  • NCC nanocrystalline cellulose
  • Such a composition typically comprises of NCC bearing hydroxyl groups and/or anionic acid groups, such as sulfate, sulfonate, phenyl sulfate, or phenyl sulfonate groups, on the crystal surfaces.
  • this invention seeks to provide a method to produce nanocrystalline cellulose (NCC) for use as antiviral agent.
  • NCC nanocrystalline cellulose
  • Yet another object of the invention is a method to produce a composition
  • NCC nanocrystalline cellulose
  • this invention seeks to provide the use of nanocrystalline cellulose (NCC) for reducing the risk of viral infections, or for treating or preventing viral infections.
  • the final aspect of the invention is the use of a composition comprising an effective amount of nanocrystalline cellulose (NCC) for reducing the risk of viral infections, or for treating or preventing viral infections.
  • this invention concerns nanocrystalline cellulose (NCC) as an antiviral compound.
  • the invention concerns a method for the preparation of a nanocrystalline cellulose (NCC) , in particular nanocrystalline cellulose (NCC) useful as an antiviral compound.
  • NCC nanocrystalline cellulose
  • This method is characterized by the steps of (a) treating native cellulose with a strong acid, preferably strong sulfuric acid, most preferably a 65 wt-% aqueous sulfuric acid solution, to dissolve the amorphous regions of the cellulose;
  • this invention concerns an antiviral composition
  • an antiviral compound comprising an antiviral compound and a carrier, wherein the antiviral compound is a
  • nanocrystalline cellulose according to any of the claims 1-9.
  • the invention concerns an antiviral fabric useful for disinfection purposes, especially for reducing the risk of viral infections in hospitals, clinics and the like, wherein said fabric is a woven or non- woven fabric immersed with an antiviral nanocrystalline cellulose (NCC) according to any of the claims 1-9 or an antiviral composition comprising antiviral nanocrystalline cellulose (NCC) and a carrier according to claim 16.
  • NCC antiviral nanocrystalline cellulose
  • the invention concerns also a method for preventing or treating viral infections in a mammal, said method comprising administering to said mammal in the need thereof an effective amount of an antiviral nanocrystalline cellulose (NCC) according to any of the claims 1-9.
  • NCC antiviral nanocrystalline cellulose
  • the present invention also concerns novel uses of nanocrystalline cellulose and of fabrics containing the same as claimed in claims 20 to 24.
  • NCC nanocrystalline cellulose
  • Figure 1 illustrates the influence of NCC derived from cotton fiber bearing sulfate groups as a function of concentration on the inhibition of SFV infection in vitro.
  • Figure 2 illustrates the effects of NCC derived from cotton fiber bearing sulfate groups (batch 1, 2 and 3) and NCC derived from Whatman filter paper bearing sulfate groups on human corneal epithelial (HCE) cell viability in vitro after 1 hour of exposure.
  • HCE human corneal epithelial
  • Figure 3 illustrates the influence of NCC derived from cotton fiber bearing sulfate groups and NCC derived from cotton fiber modified with phenyl sulfonate groups (NCC-SPTC) (0,3 % wt.) on the inhibition of SFV infection in vitro at different SFV concentrations.
  • Figure 4 illustrates the effects of NCC derived from cotton fiber modified with phenyl sulfonate (NCC-SPTC) and (NCC-EBEA) groups on human corneal epithelial (HCE) cell viability in vitro after 1 hour of exposure.
  • NCC-SPTC phenyl sulfonate
  • NCC-EBEA human corneal epithelial
  • Figure 5 illustrates the effects of NCC derived from cotton fiber after desulfation
  • NCC-DES human corneal epithelial
  • Nanocrystalline cellulose herein refers to crystalline cellulose in which the crystals are of a particle size on the nano scale, i.e. from 5 nm to 1000 nm. In this respect the particle size is the dimension corresponding to the diameter of a sphere encasing the nanop article.
  • Nanocrystalline cellulose is extracted as a colloidal dispersion by acid hydrolysis, typically sulfuric or hydrochloric acid, of cellulosic materials, such as cotton fiber, filter paper, wood pulp, bacteria, or sea animals called tunicates.
  • NCC consists of cellulose, a linear polymer with ⁇ (1->4) linked D-glucose units, the chains of which are arranged in crystalline and amorphous domains.
  • NCC is characterized by high crystallinity ( ⁇ 85 %) which approaches the theoretical limit of cellulose chains.
  • NCC obtained via sulfuric hydrolytic extraction has a molecular weight in the range of 15,000 to 50,000 g/mol, and 2 to 7 % sulfation (sulfate groups) per
  • NCC comprises crystallites whose physical dimension ranges from 5-10 nm in cross- section and 50-1000 nm in length, depending on the cellulosic material used in the extraction. These negatively charged crystallites can be dispersed in water, or other solvents, or dried to form solid powder, e.g. by freeze-drying.
  • the NCC according to this invention comprises rod- shaped nanoparticles, derived from the crystalline regions of native cellulose.
  • the NCC is in native cellulose I form.
  • anionic groups are bound to the crystal surfaces either directly or via a spacer, such as a spacer comprising amine groups.
  • a spacer such as a spacer comprising amine groups.
  • a suitable spacer can be created by reacting desulfated nanoparticles first with a compound containing epoxides, followed by a compound comprising amine groups. Then this compound is reacted with an appropriate reagent to substitute at least part of the hydroxyl groups with other anionic groups, preferably sulfonate, phenyl sulfate or phenyl sulfonate groups. In this way, a spacer is created between the anionic substituents and the surface of the nanocrystalline cellulose (NCC).
  • epoxides and spacer-forming amine groups can be mentioned epichlorohydrin and 2,2'-(ethylenedioxy)bis(ethylamine) (EBEA), respectively.
  • EBEA 2,2'-(ethylenedioxy)bis(ethylamine)
  • Surface sulfate groups can be selectively removed from NCC via alkali treatment at elevated temperatures, which provides an abundance of hydroxyl groups and low surface charge for further derivatization [Kloser, E. et al., Langmuir 2010, 26, 13450-13456].
  • NCC can then be derivatized with other target- specific
  • NCC phenyl sulfonate groups by reaction of 4-sulfophenyl isothiocyanate sodium salt monohydrate (4-SPITC) with surface hydroxyl groups or amine derivatives of NCC under alkaline conditions.
  • SFV Semliki Forest Virus
  • the antiviral composition comprising the NCC and a carrier can be either a pharmaceutical formulation to be administered to a mammal, or a non- pharmaceutical composition such as a disinfectant.
  • the pharmaceutical formulation can be, for example,
  • a topical formulation such as a cream, ointment, lotion, suspension,
  • parenteral formulation such as an intravenous, intramuscular, intranasal, intracranial, intraperitoneal, or subcutaneous formulation; or
  • a solid or liquid oral formulation such as a powder, tablet, capsule,
  • the typical dose of the antiviral NCC depends on the administration route, the viral infection and the severity thereof.
  • the antiviral compositions can additionally comprise other active ingredients.
  • the invention will be described more in detail by reference to the experiments.
  • the experimental results indicate that the inhibition of SFV infection of primate cells in vitro is highly dependent on the concentration of NCC. In this case, at a concentration of 0.20 % wt. NCC, almost 100 % inhibition of SFV is achieved.
  • the experimental results indicate that all batches of NCC derived from cotton fiber and NCC derived from Whatman filter paper are non- cytotoxic at concentrations showing the inhibition of SFV infection because human corneal epithelial (HCE) cell viability is equal to or higher than 80 % after 1 hour of exposure in vitro.
  • HCE corneal epithelial
  • NCC derived from cotton fiber modified with phenyl sulfonate groups (NCC-SPTC) at 0,3 % wt. is effective at almost fully (> 90%) inhibiting SFV at 3,25* 10 7 PFU/ml, while unmodified NCC derived from cotton fiber is effective at almost fully (90%) inhibiting SFV at 3,25* 10 5 PFU/ml.
  • NCC derived from cotton fiber modified with phenyl sulfonate groups is a more effective anti-viral compound compared to NCC derived from cotton fiber bearing sulfate groups.
  • the anti- viral activity can be fine tuned.
  • phenyl sulfonate groups have similar chemical structure to sulfated tyrosine residues of proteins, thus are considered "tyrosine sulfate mimetic" functionalities.
  • NCC derived from cotton fiber bearing sulfate groups (batch 1 and 2), NCC derived from cotton fiber bearing phenyl sulfonate groups (NCC-SPTC and NCC-EBEA) and NCC derived from cotton fiber after desulfation (NCC-DES) all are able to inhibit SFV infection of primate cells in vitro.
  • NCC-DES stands for desulfated NCC
  • NCC-SPTC stands for stands for NCC bearing phenyl sulfonate groups directly bound to the crystal surfaces of NCC
  • NCC-EBEA stands for stands for NCC bearing phenyl sulfonate groups bound via an EBEA spacer to the crystal surfaces of NCC.
  • EBEA stands for 2,2'-(ethylenedioxy)bis(ethylamine).
  • NCC derived from cotton fiber modified with phenyl sulfonate groups NCC-SPTC and NCC-EBEA
  • HCE corneal epithelial
  • NCC derived from cotton fiber after desulfation are non-cytotoxic at 0,1 % wt. because human corneal epithelial (HCE) cell viability is equal to or higher than 80 % after 1 hour of exposure in vitro.
  • HCE human corneal epithelial
  • NCC modified with anionic acid groups Cotton NCC, Whatman NCC, NCC-SPTC, NCC-EBEA is less cytotoxic to HCE cells at 0,3 and 0,4 % wt than NCC after desulfation (see Figure 2 and 4).
  • Table 1 summarizes the influence of NCC derived from cotton fiber bearing sulfate groups (batch 1 and 2), NCC derived from cotton fiber bearing phenyl sulfonate groups (NCC-SPTC and NCC-EBEA) and NCC derived from cotton fiber after desulfation (NCC-DES) as a function of concentration on the inhibition of SFV infection in vitro. Samples containing only buffer and viral vector were used as a control.
  • NCC bearing sulfate groups almost 100 % inhibition is achieved at 0,2 % wt.
  • NCC bearing phenyl sulfonate groups NCC-SPTC and NCC-EBEA
  • NCC-SPTC and NCC-EBEA almost 100 % inhibition is achieved at 0,1 % wt.
  • NCC is obtained from Whatman 1 filter paper or cotton fibers by acid hydrolysis with 65 wt% aqueous sulfuric acid solution (45 °C, 45 minutes). The resulting dispersion is diluted and filtered into ice cubes and washed with distilled water until neutral pH by successive centrifugations at 12,000 rpm at 4 °C for 20 minutes. Finally, dialysis for one week against distilled water with a 12,400 MWCO dialysis membrane is performed to remove trace amounts of residual sulfuric acid.
  • NCC-DES Removal of sulfate groups derived from sulfuric acid hydrolysis of NCC is necessary to obtain the maximum number of hydroxyl groups.
  • Aqueous dispersions of NCC are treated in 1 M NaOH at 60 °C for 5 hours. Subsequently, the reaction is quenched by a 10-fold dilution with distilled water, centrifuged at 12,000 rpm at 4 °C for 20 minutes, re-dispersed and dialyzed against distilled water for one week to remove traces of base. These samples are referred to as NCC-DES.
  • 4-sulfophenyl isothiocyanate sodium salt monohydrate (4-SPITC) is added and allowed to react at 40 °C for 20 hours. Subsequently, the reaction is quenched by a 10-fold dilution with distilled water, centrifuged at 12,000 rpm at 4 °C for 20 minutes, re-dispersed and dialyzed against distilled water for one week to remove residual reactants and traces of base. These samples are referred to as NCC-SPTC.
  • NCC is solvent-exchanged from water to acetone to anhydrous dimethyl sulfoxide (DMSO) by successive centrifugations at 12,000 rpm at 4 °C for 20 minutes.
  • DMSO dimethyl sulfoxide
  • CDI 1,1 '-carbonyldiimidazole
  • EBEA 2,2'-(ethylenedioxy)bis(ethylamine)
  • Samples are buffered with 50 mM Tris-HCl. Final buffer concentration is 10 mM for Whatman NCC samples and 50 mM for Cotton NCC samples. pH is adjusted to 7.8. Samples diluted with 10 mM Tris-HCl buffer.
  • NCC and Semliki Forest virus (SFV) vector VA7-EGFP stock are mixed together, for example 100 ⁇ l both, so final volume is 200 ⁇ l.
  • NCC concentration and virus concentration both drop to half because of dilution (for example NCC derived from cotton fiber 0,73% ⁇ 0,365%).
  • Solutions are incubated in refrigerator overnight and next day the number of infectious virus particles is measured. Antiviral activity will be seen as a loss of infectious particles. Number of infectious particles is measured by plaque titer protocol. Number of infectious virus particles is related to inhibition (i.e. 100% inhibition represents complete loss of viral activity).
  • NCC nanocrystalline cellulose
  • Vero (B) cells or human corneal epithelial (HCE) cells are treated with the NCC samples for 1 hour.
  • Cells are washed with phosphate buffer solution and death of cells is quantified with MTT assay (colorimetric assay), wherein at least 80 % cell viability indicates non-cytotoxicity.
  • MTT assay colorimetric assay
  • the antiviral fabric useful for disinfection purposes, can be used, for example, in masks, air cleaning filters, gloves, sheets, curtains, wears and protective cloths, and the like. Further contemplated applications include uses in furniture, door handles, sanity rooms and various surfaces and equipment which are being manipulated and touched by a plurality of users. NCC can be used as a disinfectant. Citation List
  • Pirrone V. et al., Antiviral Res. 2011, 90, 168-182.
  • Van Damme L. et al., N. Engl. J. Med. 2008, 359, 463-472.

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Abstract

La présente invention concerne de la cellulose nanocristalline (NCC) en tant que composé antiviral, des procédés de préparation d'une telle NCC, des compositions antivirales de telles NCC conjointement à un support, et des utilisations de telles NCC à des fins médicales ou de désinfections.
PCT/FI2013/050979 2013-03-21 2013-10-10 Cellulose nanocristalline (ncc) en tant que composé antiviral WO2014147287A1 (fr)

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CN110818806A (zh) * 2019-09-26 2020-02-21 陕西科技大学 一种水可再分散纤维素纳晶的制备方法
JP2020172446A (ja) * 2019-04-08 2020-10-22 フタムラ化学株式会社 細胞賦活剤及びヒアルロン酸分解抑制剤

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CN110446722A (zh) * 2017-01-16 2019-11-12 株式会社Kri 硫酸酯化修饰纤维素纳米纤维和纤维素纳米纤维的制造方法
CN110446722B (zh) * 2017-01-16 2024-06-11 横河电机株式会社 硫酸酯化修饰纤维素纳米纤维和纤维素纳米纤维的制造方法
JP2020172446A (ja) * 2019-04-08 2020-10-22 フタムラ化学株式会社 細胞賦活剤及びヒアルロン酸分解抑制剤
JP7283192B2 (ja) 2019-04-08 2023-05-30 横河電機株式会社 細胞賦活剤及びヒアルロン酸分解抑制剤
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