Nanoparticle composition, antibacterial, antifungal, and antiviral agent, antibacterial, antifungal, and antiviral paint, antibacterial, antifungal, and antiviral agent preparation kit, and method for producing the nanoparticle composition.

Abstract

To provide: a nanoparticle composition which has adjustable solubility and dispersibility in a solvent and has antimicrobial activity against a variety of pathogenic microbes; and an antibacterial antifungal antiviral agent, an antibacterial antifungal antiviral coating, an antibacterial antifungal antiviral agent preparation kit, and a nanoparticle composition production method.SOLUTION: A nanoparticle composition comprises: a polymer which has a repeating structural unit with a guanidino group or biguanidino group, and has antibacterial activity and antiviral activity; and a compound which has an acidic proton and has antifungal activity.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to a nanoparticle composition, an antibacterial, antifungal and antiviral agent, an antibacterial, antifungal and antiviral paint, a kit for preparing an antibacterial, antifungal and antiviral agent, and a method for producing a nanoparticle composition.

Background Art

[0002] In order to easily impart antibacterial properties to various products, a paint containing an antibacterial component is applied to the surface of the product after production. As the antibacterial component, a compound having a guanidino group or a biguanidino group as a repeating structural unit is widely used. For example, the hydrochloride of polyhexamethylene biguanide (PHMB) is effective against a wide range of bacteria by disrupting the cell membrane by the cation derived from the biguanidino group. Furthermore, PHMB also has antiviral activity.

[0003] Due to the increasing trend towards cleanliness, the demand for products having not only antibacterial properties but also antifungal properties is increasing. The above-mentioned PHMB has poor antifungal effects. As an antifungal agent, thiabendazole (TBZ), which shows high antibacterial properties against a wide range of fungi, is known. However, TBZ shows almost no antibacterial properties against bacteria.

[0004] Ortho-phenylphenol (OPP) and 2-mercaptopyridine-N-oxide (pyrithione, PT) show antibacterial properties against fungi and bacteria. However, the types of bacteria and fungi against which OPP and PT show antibacterial properties are few. So far, no single compound effective against a wide range of bacteria and fungi has been known.

[0005] Many compositions combining an antibacterial agent and an antifungal agent are known. For example, Patent Document 1 discloses a composition for preventing discoloration-causing fungi in wood, which is obtained by mixing an aqueous solution of PHMB hydrochloride and TBZ in the presence of a surfactant. Patent Document 2 discloses a topical composition for use in the treatment of fungal nail infections, which contains nanoparticles formed from a PHMB salt and an antifungal agent.

Prior Art Documents

Patent Documents

[0006] [Patent Document 1] Japanese Patent Publication No. 2020-090546 [Patent Document 2] Japanese Patent Publication No. 2019-218393 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] PHMB is water-soluble but practically insoluble in organic solvents, especially highly lipid-soluble solvents. When dissolving an antifungal agent in a solvent along with PHMB, considering the dispersibility of both PHMB and the antifungal agent, it becomes necessary to use an antifungal agent with similar solubility to PHMB. TBZ has low solubility in water and organic solvents. Thus, it is difficult to use PHMB and TBZ, etc., in combination in paints and other applications due to their significantly different solvent solubility. Furthermore, even if antibacterial and antifungal agents with similar solvent solubility are used, the limited solvents restrict the types of paints that can be applied.

[0008] The present invention has been made in view of the above circumstances, and aims to provide a nanoparticle composition, an antimicrobial agent, an antimicrobial, antifungal, and antiviral paint, an antimicrobial, antifungal, and antiviral agent preparation kit, and a method for producing a nanoparticle composition, which can adjust the solubility and dispersibility in a solvent and exhibit antimicrobial activity against a wide range of pathogenic microorganisms. [Means for solving the problem]

[0009] A nanoparticle composition according to the first aspect of the present invention is Polyhexamethylene biguanide and, At least one selected from the group consisting of thiabendazole, orthophenylphenol, and 2-mercaptopyridine-N-oxide. Compounds and Includes fruit, The polyhexamethylene biguanide and the compound form nanoparticles with a particle size of 1 to 1000 nm through ionic bonding. .

[0012] Furthermore, the nanoparticle composition according to the first aspect of the present invention is It also contains acidic components, may also be.

[0013] Also, the acid dissociation constant pKa of the acidic component is 10 or less, may also be.

[0014] Also, the acidic component is at least one selected from the group consisting of hydrochloric acid, benzoic acid, oleic acid, lauric acid, lactic acid, and acetic acid, may also be.

[0015] The antibacterial, antifungal, and antiviral agent according to the second aspect of the present invention includes the nanoparticle composition according to the first aspect of the present invention.

[0016] The antibacterial, antifungal, and antiviral paint according to the third aspect of the present invention includes the nanoparticle composition according to the first aspect of the present invention.

[0017] The antibacterial, antifungal, and antiviral agent preparation kit according to the fourth aspect of the present invention the nanoparticle composition according to the first aspect of the present invention, and an acidic component to be mixed with the nanoparticle composition, and comprises.

[0018] The method for producing a nanoparticle composition according to the fifth aspect of the present invention Polyhexamethylene biguanide and At least one selected from the group consisting of thiabendazole, orthophenylphenol, and 2-mercaptopyridine-N-oxide. a compound to be mixed under alkaline conditions Furthermore, the polyhexamethylene biguanide and the compound form an ionic bond, thereby creating nanoparticles with a particle size of 1 to 1000 nm. including a mixing step.

Advantages of the Invention

[0019] The nanoparticle composition according to the present invention can adjust the solubility and dispersibility in a solvent and exhibits antimicrobial activity against a wide range of pathogenic microorganisms.

Brief Description of the Drawings

[0020] [Figure 1]This figure shows the 1H NMR (Nuclear Magnetic Resonance) spectrum of the composition according to Example 5. [Figure 2] This figure shows the 1H NMR spectrum of the composition according to Example 6. [Figure 3] This figure shows the 1H NMR spectrum of the composition according to Example 7. [Figure 4] This figure shows the particle size distribution by scattering intensity for the composition according to Example 6. [Modes for carrying out the invention]

[0021] Embodiments of the present invention will be described with reference to the drawings. However, the present invention is not limited to the embodiments and drawings described below. In the embodiments described below, expressions such as “having,” “including,” or “containing” also include the meaning of “consisting of” or “composed of.”

[0022] (Embodiment 1) The nanoparticle composition according to this embodiment comprises a polymer having antibacterial and antiviral activity, and a compound having antifungal activity. The polymer has guanidino groups or biguanidino groups as repeating structural units. The polymer is also called a polymer or oligomer. Preferably, the polymer has C2-C2 groups bonded to the guanidino groups or biguanidino groups in its repeating structure. 140 Aliphatic groups containing carbon atoms, such as C2, C3, C4, C5, C6, C7, C8, C9 or C 10 It contains alkyl groups such as the above. Preferably, the polymer has a repeating structural unit consisting of a guanidino group or biguanidino group bonded to a methylene group. The number of methylene groups in the repeating structural unit is arbitrary, but for example, it can be 2 to 10, 3 to 8, or 4 to 6, and is particularly preferably 3 or 6.

[0023] Polymers having guanidino groups as repeating structural units include, for example, polyhexamethyleneguanidine (PHMG) shown in Formula 1. Polymers having biguanidino groups as repeating structural units include, for example, PHMB shown in Formula 2, polyaminopropyl biguanide (PAPB) shown in Formula 3, and chlorhexidine. In Formulas 1 to 3, "n" indicates the degree of polymerization, which is the number of repeating units constituting the polymer.

[0024] [ka]

[0025] [ka]

[0026] [ka]

[0027] Preferably, n is 2-40, 3-30, 4-20, or 5-15, preferably 8-12. The polymer used in the nanoparticle composition according to this embodiment may be a mixture of polymers with different values ​​of n, or it may be a polymer with the same value of n. The nanoparticle composition may contain a combination of multiple types of the above-mentioned polymers as the polymer.

[0028] Compounds having antifungal activity are not particularly limited as long as they have an acidic proton and can become anions upon alkaline treatment. Examples of such compounds include imidazole, thiazole, isothiazolin, phenol, pyrithione, triazine, nitrile, iodine, anilide, amino acid, thiocarbamate, ester, sulfamide, and azole compounds with antifungal activity.

[0029] For example, imidazole compounds include TBZ, carbentadium, 2-methylcarbonylaminobentimidazole, and their derivatives. Thiazole compounds include 2-(4-thiocyanomethylthio)bentthiazole and its derivatives. Isothiazoline compounds include 2-n-octyl-4-isothiazoline-3-one (OIT) and its derivatives. Phenol compounds include OPP, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, and their derivatives.

[0030] The pyrithione compounds are PT, 2,2'-dithiobispyridine-1-oxide, and their derivatives, as shown in Formula 7. The triazine compounds are hexahydro-1,3,5-tris(2-hydroxyethyl)-S-triazine and its derivatives. The nitrile compound is 2,4,5,6-tetrachloroisophthalonitrile. The iodine compounds are 3-iodo-2-propylbutylcarbamate, diiodomethyl p-tolylsulfone, and their derivatives.

[0031] Anilide compounds include trichlorocarbanilide and its derivatives. Amino acid compounds include alkyldiaminoglycine and its derivatives. Thiocarbamate compounds include N-methyldithiocarbamic acid and its derivatives. Ester compounds include p-hydroxybenzoic acid esters, fatty acid monoglycerides, sucrose fatty acid esters and their derivatives.

[0032] Sulfamide compounds include N-(fluorodichloromethylthio)phthalimide, N,N-dimethyl-N'-phenyl-N'-(fluorodichloromethylthio)sulfamide, N-[dichloro(fluoro)methyl]sulfanyl-N',N'-dimethyl-Np-tolylsulfamide, forpet, and their derivatives. Azole compounds include tebuconazole, hexaconazole, propinazole, diproconazole, and their derivatives.

[0033] Preferably, compounds having antifungal activity include TBZ (Formula 4), OPP (Formula 5), ​​and PT (Formula 6).

[0034] [ka]

[0035] The compound used in the nanoparticle composition according to this embodiment is not limited to one type, but may be used in combination of multiple types. Preferably, the compound is at least one selected from the group consisting of TBZ, OPP, and PT.

[0036] The composition ratio of polymer to compound in the nanoparticle composition according to this embodiment is not particularly limited, and is, for example, 2 to 10:1 or 4 to 8:1 in molar ratio (polymer:compound, where the number of moles of polymer is based on the molecular weight of the repeating structural units of the polymer), preferably 2 to 1 or 5 to 1.

[0037] Next, a method for producing the nanoparticle composition according to this embodiment will be described. The method for producing the nanoparticle composition includes the step of mixing the polymer and compound described above under alkaline conditions. Alkaline conditions mean that the pH is in the range of 10 to 14, preferably 12 to 14. Below, the method for producing the nanoparticle composition will be described using the case in which PHMB is used as the polymer as an example.

[0038] First, the PHMB salt is dissolved in a solvent, and an alkali is added while stirring (alkali treatment). The solvent used to dissolve the PHMB salt is not particularly limited as long as it is a solvent other than water in which the PHMB salt is soluble. Examples of solvents include aliphatic alcohols, glycols, and glycol ethers. Ethanol is preferably used as the solvent. The alkali used in the alkali treatment is not particularly limited. Preferably, the alkali is added as a solution obtained by dissolving the alkali in the solvent in which the PHMB salt is dissolved.

[0039] After further stirring of the mixture, the salt crystals formed in the mixture are removed by filtration to obtain a PHMB solution. A suspension of a compound having antifungal activity is added to the solution while stirring, and the mixture is stirred further. Preferably, the suspension is a suspension of the compound in a solvent in which the PHMB salt is dissolved. The nanoparticle composition according to this embodiment is obtained by the above steps.

[0040] As shown in the examples below, ionic nanoparticle compositions can be prepared by combining a polymer having a guanidino group or a biguanidino group with a compound having an acidic proton. The nanoparticle compositions according to this embodiment exhibit antibacterial and antiviral activity derived from the polymer, and antifungal activity derived from the compound.

[0041] According to the method for producing the nanoparticle composition of this embodiment, by mixing the polymer and the compound under alkaline conditions, a composition that results in a uniform solution can be obtained, even with a combination of PHMB and TBZ, for which it has been difficult to obtain a uniform solution until now.

[0042] The nanoparticle composition according to this embodiment is a capsule-structure particle in which a compound is surrounded by a polymer with a hydrophobic substructure facing outward and an ionic substructure facing inward. The nanoparticle composition is formed by the ionic bonding of a polymer having antibacterial and antiviral activity with a compound having antifungal activity. The particles are fine particles with a particle size on the order of nanometers. The particle sizes of the nanoparticles are, for example, 1 to 1000 nm, 2 to 100 nm, 3 to 50 nm, or 4 to 10 nm.

[0043] The particle size of nanoparticles can be measured by known methods such as sieving, sedimentation, microscopy, dynamic light scattering (DLS), laser diffraction / scattering, electrical resistance testing, transmission electron microscopy, and scanning electron microscopy. Depending on the measurement method, the particle size can be expressed as the equivalent diameter of a stalk, the equivalent diameter of a circle, or the equivalent diameter of a sphere. Alternatively, the particle size may be expressed as the average particle size, volume average particle size, or area average particle size, based on the average of multiple particles measured. Furthermore, the particle size may be the average particle size calculated from the number distribution based on measurements such as laser diffraction / scattering.

[0044] The nanoparticle composition according to this embodiment can have its solubility controlled by further including an acidic component as needed. Preferably, the acid dissociation constant pKa of the acidic component is 10 or less. Here, "pKa" means "acid dissociation constant in water," and more specifically, "acid dissociation constant in water at 25°C." For acidic components whose acid dissociation constant cannot be measured in water, it means "acid dissociation constant in dimethyl sulfoxide (DMSO)," and for acidic components whose acid dissociation constant cannot be measured even in DMSO, it means "acid dissociation constant in acetonitrile."

[0045] For example, the acidic component may be an inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid; a carboxylic acid such as acetic acid, benzoic acid, sorbic acid, oleic acid, and lauric acid; an amino acid such as phenylalanine and phenylglycine; a hydroxycarboxylic acid such as glycolic acid, tartaric acid, and lactic acid; an aromatic sulfonic acid such as toluenesulfonic acid; and an alkylsulfonic acid such as methanesulfonic acid. Preferably, the acidic component is at least one selected from the group consisting of hydrochloric acid, benzoic acid, oleic acid, lauric acid, lactic acid, and acetic acid. The acidic component is not limited to one type, but may be used in combination with multiple types.

[0046] An example of a method for producing the nanoparticle composition according to this embodiment, in which an acidic component is included, is provided. In this method for producing the nanoparticle composition, the polymer salt and the compound are mixed under alkaline conditions. In the production method described below, PHMB hydrochloride and hydrochloric acid are used as the polymer salt and acidic component, respectively.

[0047] First, the compound is suspended in a solvent, and alkali is added while stirring to obtain an alkali salt solution of the compound. The PHMB salt is dissolved in the solvent and mixed with the alkali salt solution of the compound while stirring. After further stirring, the resulting salt crystals are removed by filtration to obtain a solution of the PHMB-compound-HCl composition. The nanoparticle composition according to this embodiment is obtained by the above steps.

[0048] When combining multiple types of compounds, the suspension or alkali salt solution of each compound may be mixed in any order. Furthermore, whether or not an acidic component is included, the ratio of each component of the nanoparticle composition according to the method for producing the nanoparticle composition according to this embodiment can be arbitrarily set by the amount of polymer or compound. The composition ratio of polymer, compound and acidic component in a nanoparticle composition containing an acidic component is not particularly limited; for example, if the compound is set to 1, the molar ratio of polymer and acidic component is 1 to 20, 2 to 10, or 3 to 5, respectively. Preferably, the composition ratio of polymer, compound and acidic component is 20:1:19, 5:1:4, or 2:1:1 in molar ratio (polymer:compound:acidic component).

[0049] Guanidino and biguanidino groups are strong bases. Polymers containing guanidino or biguanidino groups are expected to form stable salts with compounds containing acidic protons. The composition ratio of the formed salt can be controlled by the amount of acidic component added, allowing for arbitrary determination of the composition ratio. Furthermore, by adding an appropriate acidic component, the physical properties of the nanoparticle composition can be altered, and its solubility in various solvents can be controlled.

[0050] The nanoparticle composition according to this embodiment can be dissolved in various solvents, such as water, alcohol, and organic solvents. Examples of solvents include alcohols such as ethanol, isopropanol, phenoxyethanol, and benzyl alcohol; glycol solvents such as ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, butylene glycol, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, dipropylene glycol monomethyl ether, and tripropylene glycol monomethyl ether; glycerin solvents such as glycerin and diglycerin; cyclic organic solvents such as dimethyl sulfoxide, N-methylpyrrolidone, and γ-butyrolactone; ester solvents such as phthalates, adipicates, and sebacates; aromatic solvents such as methylnaphthalene, phenylxylethane, and alkylbenzenes; aliphatic hydrocarbon solvents such as normal paraffins and isoparaffins; and rapeseed oil, cottonseed oil, soybean oil, and castor oil. These solvents may be used individually or in combination of two or more types.

[0051] The nanoparticle composition according to this embodiment exists as nanometer-sized particulate matter in solution and is thought to gradually decompose into polymers and compounds upon contact with acidic substances such as carbonic acid derived from carbon dioxide in the air, thereby exhibiting antibacterial and antifungal properties.

[0052] The nanoparticle composition according to this embodiment exhibits antibacterial activity against, for example, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Legionella, Listeria, Proteus, Pseudomonas aeruginosa, Salmonella, and Streptococcus. Furthermore, the nanoparticle composition exhibits antifungal activity against, for example, Aspergillus niger, Chaetomium globosum, Penicillium citrinum, Rhizopus oryzae, and Cladosporium sphaerospermum.

[0053] The nanoparticle composition according to this embodiment exhibits antiviral activity against, for example, influenza virus, feline calicivirus, rotavirus, norovirus, coronavirus, and novel coronavirus.

[0054] As described in detail above, the nanoparticle composition according to this embodiment can have its solubility and dispersibility in solvents adjusted. Furthermore, as shown in the following examples, the nanoparticle composition exhibits antibacterial activity against a wide range of bacteria and fungi, and antiviral activity against multiple viruses.

[0055] In another embodiment, an antimicrobial, antifungal, and antiviral agent is provided that contains the nanoparticle composition according to this embodiment as an active ingredient. The antimicrobial, antifungal, and antiviral agent may further contain a buffer, excipients, binders, oil, water, emulsifiers, glycerin, antioxidants, preservatives, permeators, and fragrances. The antimicrobial, antifungal, and antiviral agent may be a paste or a suspension. The antimicrobial, antifungal, and antiviral agent may be in the form of a lotion, liquid, cream, ointment, or spray.

[0056] The antimicrobial, antifungal, and antiviral agent may be applied to areas infected with fungi, bacteria, or viruses in animals, including humans. When the antimicrobial, antifungal, and antiviral agent is applied to the skin, it can be formulated as an ointment in which the nanoparticle composition is suspended or dissolved in, for example, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. The antimicrobial, antifungal, and antiviral agent can also be formulated as a lotion or cream in which the nanoparticle composition is suspended or dissolved in, for example, mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0057] The antibacterial, antifungal, and antiviral agent can be applied or sprayed onto an object where the growth of fungi, bacteria, and viruses is to be prevented or suppressed, thereby preventing or suppressing the growth of fungi, bacteria, and viruses on the surface of the object by exposing the surface to the antibacterial, antifungal, and antiviral agent.

[0058] Furthermore, this antibacterial, antifungal, and antiviral agent can be used to treat or prevent fungal infections such as fungal nail infections, athlete's foot, and fungal skin infections. It can also be used to treat or prevent various diseases caused by bacterial or viral infections.

[0059] In another embodiment, an antibacterial, antifungal, and antiviral agent preparation kit is provided. The antibacterial, antifungal, and antiviral agent preparation kit comprises a nanoparticle composition according to Embodiment 1, particularly a nanoparticle composition that does not contain an acidic component, and an acidic component to be mixed with the nanoparticle composition. As described above, by adding an acidic component, the physical properties of the nanoparticle composition can be changed and its solubility in various solvents can be controlled. Therefore, by adjusting the type and amount of the acidic component according to the solvent in which the nanoparticle composition is dissolved, solubility suitable for the solvent can be imparted to the nanoparticle composition.

[0060] The antibacterial, antifungal, and antiviral agent preparation kit contains an acidic component in a form separate from the nanoparticle composition. For example, in the antibacterial, antifungal, and antiviral agent preparation kit, the nanoparticle composition is held in a first container, and the acidic component is held in a second container different from the first container. For example, the first container holds a nanoparticle composition obtained by mixing a suspension of the compound with a PHMB solution obtained by removing the salt crystals produced by the alkaline treatment of the PHMB salt by filtration. On the other hand, the second container holds the acidic component. In this case, the user can prepare the antibacterial, antifungal, and antiviral agent by mixing the nanoparticle composition held in the first container and the acidic component held in the second container at the time of use.

[0061] When antibacterial, antifungal, and antiviral agents are used, for example, when added to paints, the solubility of the antibacterial, antifungal, and antiviral agents can be adjusted according to the paint by mixing in appropriate acidic components according to the paint's composition. The antibacterial, antifungal, and antiviral agent preparation kit may contain not just one type, but multiple types of acidic components. This allows users to select or combine acidic components according to the application of the antibacterial, antifungal, and antiviral agent.

[0062] The antibacterial, antifungal, and antiviral agent preparation kit may include instructions that describe mixing the nanoparticle composition with an acidic component. The instructions may also specify the type and amount of the acidic component to be used for each application, as well as the stirring time after mixing.

[0063] (Embodiment 2) The antibacterial, antifungal, and antiviral coating according to this embodiment includes the nanoparticle composition according to Embodiment 1 described above. In addition to the nanoparticle composition, the antibacterial, antifungal, and antiviral coating may also contain known coating components depending on the purpose. Examples of coating components include binders, solvents, colorants, pigments, fillers, viscosity modifiers, surface modifiers, dispersants, surfactants, UV absorbers, light stabilizers, and defoamers. The content of each component can be arbitrarily adjusted depending on the purpose of addition, etc.

[0064] The binder can be any known binder as a component of paint, and inorganic or organic binders are used. The binder has the function of fixing the nanoparticle composition in the paint film. The binder can be in any form, including solvent type, emulsion (dispersion) type, solvent-free type, one-component type, multi-component type, and powder type.

[0065] Examples of inorganic binders include silica binders, zirconia binders, alumina binders, titania binders, and water glass (sodium silicate, potassium silicate, and lithium silicate).

[0066] Examples of organic binders include (meth)acrylic polymers, styrene polymers, vinyl acetate polymers, rubber-based polymers, vinyl chloride polymers, vinyl alcohol-based polymers, polyolefin-based polymers, polyester-based polymers, fluororesin-based polymers, silicone-based polymers, urethane-based polymers, epoxy-based polymers, core-shell polymers, and curable compound systems having ethylenically unsaturated bonds (such as (meth)acrylate monomer systems and vinyl monomer systems).

[0067] The organic binder may further contain a curing agent used in the paint industry. Examples of curing agents include polyisocyanate compounds, polyol compounds, polycarboxylic acid compounds, melamine compounds, epoxy compounds, aldehyde compounds, and aziridine compounds.

[0068] The binder content can be 1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass, relative to the total antibacterial, antifungal, and antiviral coating, from the viewpoint of antibacterial, antifungal, and antiviral properties, dispersibility, and film-forming properties. Furthermore, the solid content ratio of the antibacterial, antifungal, and antiviral coating can be 50 to 99% by mass, preferably 70 to 97% by mass, and more preferably 80 to 95% by mass. If the binder content is too high, the desired antibacterial, antifungal, and antiviral activity may not be obtained, which may be disadvantageous in terms of coating strength and cost. If the binder content is too low, the desired antibacterial, antifungal, and antiviral activity may not be obtained, which may cause problems in terms of coating strength and dispersibility.

[0069] The solvent is not particularly limited, and water, organic solvents, and carbon dioxide are used for purposes such as viscosity adjustment and dilution. Examples of organic solvents include alcohols such as ethanol, propanol, and butanol; ketones such as acetone, methyl ethyl ketone, and cyclohexanone; halogenated hydrocarbons such as methylene chloride; aromatic hydrocarbons such as benzene, toluene, and xylene; amides such as methylpyrrolidone and dimethylacetamide; esters such as ethyl acetate and butyl acetate; ethers such as diethyl ether, tetrahydrofuran, and dioxane; glycol ethers such as ethylene glycol monomethyl ether and ethylene glycol dimethyl ether; cyclic esters such as γ-butyrolactone; and aliphatic hydrocarbons such as mineral spirits.

[0070] The colorants are not particularly limited, and inorganic coloring pigments, organic coloring pigments, fluorescent pigments, luminous pigments, colored resin particles, and dyes can be used for the purpose of imparting a desired color tone to the coating film. Among these, the pigments may be self-dispersing types in which at least one hydrophilic group or lipophilic group is directly bonded to the surface of the pigment or by various atomic groups, or the surface of the pigment may be modified with various surface modifiers.

[0071] Examples of fillers include talc, mica, barium sulfate, clay, calcium carbonate, kaolin, silica, bentonite, barium carbonate, zirconia, and alumina.

[0072] Examples of viscosity modifiers include cellulose-based, polyamine-based, starch-based, alginic acid-based, fatty acid ester-based, polyvinyl alcohol-based, and polyacrylic acid (salt)-based materials.

[0073] The substrate to which the antibacterial, antifungal, and antiviral coating according to this embodiment is applied can be any material to which antibacterial, antifungal, and antiviral properties are desired, and to which the coating can be applied. The material constituting the substrate is not particularly limited, but examples include metals such as iron and aluminum, glass, concrete, various plastics, paper, and wood. Alternatively, it may be a composite material such as a laminate or composition containing one or more of these materials.

[0074] The objects to which antibacterial, antifungal, and antiviral paints are applied are not particularly limited, but examples include various items installed in medical institutions, commercial facilities, schools, public facilities, food factories, nursing care facilities, cooking facilities, food and beverage-related facilities, and transportation facilities. Examples of such items include doors, doorknobs, handrails, handles, walls, glass, building materials, tables, chairs, home appliances, writing instruments, stationery, office supplies, medical equipment, push buttons, personal computers, keyboards, mice, touch panels, mobile communication devices, electronic medical records, display devices, desks, drawers, files, name tags / signboards, operation buttons and switches, etc.

[0075] The method for forming a coating film with antibacterial, antifungal, and antiviral paint according to this embodiment can employ a general method for applying the antibacterial, antifungal, and antiviral paint coating film to an article or substrate, depending on the shape of the article and substrate or its intended use. Examples of coating film forming methods include air spraying, airless spraying, electrostatic, rotary atomization, brushes, rollers, hand guns, multi-purpose guns, dipping, roll coaters, curtain flow coaters, roller curtain coaters, die coaters, and inkjet printers. Preferably, the coating film forming method is air spraying, airless spraying, electrostatic, rotary atomization, brushes, hand guns, multi-purpose guns, and inkjet printers.

[0076] When applying antibacterial, antifungal, and antiviral coatings to a substrate, if the surface is contaminated with oil or other contaminants, it is preferable to degrease and clean the substrate surface with alcohol or the like. To improve adhesion and corrosion resistance between the substrate and the coating film, known surface treatments such as roughening, plasma treatment, flame treatment, and primer treatment may be performed.

[0077] After applying the antibacterial, antifungal, and antiviral paint, the paint film may be dried by means of room temperature drying or forced drying to form the painted object. In the case of room temperature drying, the painted object should be left to stand at room temperature (for example, between 10 and 40°C). In the case of forced drying, drying may be done using a blower or the like, or it may be baked dry by heating at a temperature above room temperature, for example, 50°C or higher for one minute or more. If the binder is curable, it may be cured by energy rays such as ultraviolet light or by heat. From the viewpoint of finish quality, it may be left to stand at room temperature beforehand before drying or curing.

[0078] In painted objects, the thickness of the coating film (dry film thickness) formed by the antibacterial, antifungal, and antiviral paint is not particularly limited and can be adjusted as appropriate according to the application. For example, the dry film thickness can be 0.1 to 1000 μm, preferably 80 μm or less, more preferably 50 μm or less, more preferably 30 μm or less, and even more preferably 1 to 20 μm.

[0079] The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples. [Examples]

[0080] A composition having the following composition was prepared as described below. The values ​​in parentheses in Table 1 indicate the molar ratio. For example, the composition of Example 1-1 has a molar ratio of PHMB to TBZ of 2:1 (the number of moles of PHMB is based on the molecular weight of the repeating structural units of PHMB).

[0081] [Table 1]

[0082] (Examples 1-1 and 1-2) 2 mL of PHMB hydrochloride aqueous solution (20% w / w) was concentrated using an evaporator and dissolved in 10 mL of ethanol. 2 mL of sodium ethoxide ethanol solution (1.0 M) was added while stirring. The mixture became a pale yellow solution and became cloudy due to the resulting sodium chloride. After stirring at room temperature for another hour, the sodium chloride crystals were removed by filtration to prepare a PHMB ethanol solution.

[0083] To an ethanol solution of PHMB, a 10 mL ethanol suspension of 1 mmol (201 mg) of TBZ was added while stirring, and the mixture was stirred at room temperature for a further 1 hour. The resulting solution was diluted with ethanol to a total volume of 55 g, and a 1.0% w / w solution was obtained as Example 1-1. In addition, to the above ethanol solution of PHMB, a 20 mL ethanol suspension of 2 mmol (402 mg) of TBZ was added while stirring, and the mixture was stirred at room temperature for a further 1 hour. The resulting solution was diluted with ethanol to a total volume of 75 g, and a 1.0% w / w solution was obtained as Example 1-2.

[0084] (Example 2) To the ethanol solution of PHMB prepared in the same manner as in Example 1-1, a 10 mL ethanol suspension of PT 2 mmol (298 mg) was added while stirring, and the mixture was stirred at room temperature for a further 1 hour. The resulting solution was diluted with ethanol to a total volume of 65 g, and a 1.0% w / w solution was obtained as Example 2.

[0085] (Example 3) Similar to Example 1-1, a 10 mL ethanol suspension of 1 mmol (201 mg) of TBZ was added to an ethanol solution of PHMB while stirring, and the mixture was stirred at room temperature for a further 1 hour. 1 mmol (149 mg) of PT was added to the resulting solution, and the mixture was stirred at room temperature for several more hours. The resulting solution was diluted with ethanol to a total volume of 70 g, and a 1.0% w / w solution was obtained as Example 3.

[0086] (Examples 4-1 and 4-2) 0.1 mmol (20 mg) of TBZ was suspended in 5 mL of ethanol, and 1 mL of sodium ethoxide ethanol solution (1.0 M) was added while stirring to prepare an ethanol solution of TBZ sodium salt. 2 mL of PHMB hydrochloride aqueous solution (20% w / w) was concentrated using an evaporator and dissolved in 10 mL of ethanol, and the ethanol solution of TBZ sodium salt was added while stirring. After stirring at room temperature for several hours, sodium chloride crystals were removed by filtration to obtain an ethanol solution of the PHMB-TBZ-hydrochloric acid (HCl) composition. The obtained solution was diluted with ethanol to a total volume of 37 g, and a 1.0% w / w solution was obtained as Example 4-1.

[0087] Using 0.4 mmol (80 mg) of TBZ and 2 mL of PHMB hydrochloride aqueous solution (20% w / w), an ethanol solution of the PHMB-TBZ-hydrochloride composition was obtained in the same manner as in Example 4-1. The obtained solution was diluted with ethanol to a total volume of 43 g, and a 1.0% w / w solution was obtained as Example 4-2.

[0088] (Examples 5-10) Similar to Example 1-1, a 10 mL ethanol suspension of 1 mmol (201 mg) of TBZ was added to an ethanol solution of PHMB while stirring, and the mixture was stirred at room temperature for a further 1 hour. 1 mmol of benzoic acid (122 mg) was added to the resulting solution, and the mixture was stirred at room temperature for several hours. The resulting solution was diluted with ethanol to a total volume of 67 g, and a 1.0% w / w solution was obtained as Example 5.

[0089] Examples 6, 7, 8, 9, and 10 were prepared in the same manner as in Example 5, except that the benzoic acid added in Example 5 was replaced with oleic acid (282 g), lauric acid (200 g), toluenesulfonic acid (172 g), lactic acid (90 g), and acetic acid (60 g), respectively.

[0090] (Confirmation of the composition ratio of the composition) The composition ratio of each component in the composition obtained above is 1 The composition was determined by 1H NMR. Deuterium methanol was used as the solvent, and the composition ratio was determined from the integrated proton signals of each component. 1 A JEOL JNM-ECX400 (manufactured by JEOL Ltd.) was used for the 1H NMR spectrometer.

[0091] (result) Examples of determining the composition ratio include those of Examples 5, 6 and 7. 1 The 1H NMR spectra are shown in Figures 1-3, respectively. Example 5 was prepared with a molar ratio of 2:1:1. The proton signals of each component in Example 5 were as follows.

[0092] PHMB:3.16ppm(brs,7H),1.53ppm(brs,9H),1.35ppm(brs s,8H), TBZ:9.09ppm(d,J=1.8Hz,1H),8.23ppm(d,J=1.8Hz,1H),7.93-7.90ppm(m,2H ), 7.59ppm (m, J=6.3, 3.2Hz, 2H), Benzoic acid: 7.39-7.30ppm (m, 4H), 7.22-7.19ppm (m, 2H).

[0093] From the integrated proton signals of each component, it was confirmed that the ratio of each component was 1.98:1.12:0.99, which is in close agreement with the ratio of each component added during preparation.

[0094] Example 6 was prepared with a molar ratio of 2:1:1. The proton signals of each component in Example 6 were as follows:

[0095] PHMB:3.17ppm(brs,7H),1.54ppm(br s,9H),1.36-1.28ppm(m,29H),TBZ:9.10ppm(d,J=2.3Hz,1H),8.24ppm(d,J=2.3Hz,1H),7.59ppm(q,J=3.1Hz,2H),7.21pp m(q,J=3.1Hz,2H), oleic acid:5.36-5.28ppm(m,2H),2.16-1.99ppm(m,6H),1.36-1.28ppm(m,29H),0.89ppm(t,J=6.9Hz,3H).

[0096] The integral values ​​of the proton signals of each component showed a ratio of 2.01:1.09:1.04. This was confirmed to be in close agreement with the ratio of each component added during preparation.

[0097] Example 7 was prepared with a molar ratio of 2:1:1. The proton signals of each component in Example 7 were as follows:

[0098] PHMB:3.14ppm(d,J=18.8Hz,6H),1.60-1.45ppm(m,11H),1.36-1.28ppm(m,15H ), TBZ:9.09ppm(d,J=1.8Hz,1H),8.23ppm(d,J=1.8Hz,1H),7.60ppm(m,J=3.2H z,2H),7.19ppm(m,J=3.1Hz,2H),lauric acid:2.13ppm(q,J=7.5Hz,2H),1.54ppm(s, 2H), 1.36-1.28ppm (m, 15H), 1.17ppm (t, J=7.1Hz, 68H), 0.93-0.85ppm (m, 3H).

[0099] The integral values ​​of the proton signals of each component showed a ratio of 1.71:1.09:1.06. This was confirmed to be in close agreement with the ratio of each component added during preparation.

[0100] (Confirmation of the composition's structure) The particle size of the composition was measured using DLS (Zetasizer Nano series Nano-ZS, manufactured by Malvern Panalytical) for the 5% ethanol solution of Example 6.

[0101] (result) As shown in Figure 4, it was confirmed that the colloidal solution consisted of fine particles with a particle size of approximately 6.4 nm. The main component of PHMB is a polymer consisting of 10 linked unit structures, with an average molecular weight of approximately 2200. Molecular simulations suggest that the chain length of PHMB is approximately 10 nm, and the chain length of oleic acid is approximately 0.2 nm. Therefore, it can be inferred that a single independent particle is composed of 2 to several PHMB molecules bonded to approximately 10 to several tens of TBZ and oleic acid molecules, respectively.

[0102] (Investigation of the properties and solubility of the composition) Table 2 shows the properties and solubility of some of the examples. The properties and solubility of the examples are mainly influenced by the acidic component combined with them. The PHMB-TBZ-HCl composition, which is the hydrochloride salt, is obtained as a pale yellow solid, and in Example 4-1, where the proportion of hydrochloride salt is high, it is soluble in water. In Example 4-2, where the proportion of hydrochloride salt is low, it is almost insoluble in water but very soluble in ethanol, yielding a solution with a maximum concentration of 15% w / w. Example 1-1, which does not contain any acidic component, is obtained as a hydrophobic pale yellow solid and is very soluble in ethanol and benzyl alcohol.

[0103] Examples 5-7, which contain benzoic acid or a long-chain fatty acid as the acidic component, yield a pale yellow solid to a pale yellow waxy substance that is well soluble in ethanol and benzyl alcohol. Example 8, which contains sulfonic acid as the acidic component, yields a highly hydrophobic pale yellow solid that is insoluble in water and ethanol but well soluble in benzyl alcohol.

[0104] [Table 2]

[0105] (Test Example 1: Antimicrobial activity test of the composition) Antimicrobial activity tests were conducted on the examples. For the antimicrobial activity test, paper discs containing the examples were placed on a test medium as samples, and antimicrobial activity was confirmed by measuring the size of the halo after 48 hours of incubation. The bacteria used in the test were two species: Staphylococcus aureus and Escherichia coli.

[0106] A culture medium was prepared by mixing 5.0g of meat extract, 10.0g of peptone, 1000mL of purified water, 15.0g of agar, 5.0g of sodium chloride, and 1000mL of physiological saline. A bacterial stock culture was added to the medium and incubated for 10 minutes. 6 The test medium was prepared by mixing the samples to a concentration of ±200,000 cells / mL. The samples from Example 4-2, etc., were diluted with DMSO or ethanol to prepare the test solution. A paper disc with a diameter of 8 mm was immersed in the test solution and air-dried on filter paper for 24 hours to prepare the test specimen.

[0107] The test medium was dispensed into a petri dish, allowed to solidify, and then the test specimen was placed on top of the medium and incubated at 34-36°C for 48 hours. After incubation, the test specimen was observed with the naked eye to check for the presence or absence of a halo. The antibacterial activity was expressed numerically according to the size of the observed halo as follows: 0: No halo was observed, 1: Halo less than 1 mm, 2: Halo 1 mm or more but less than 3 mm, 3: Halo 3 mm or more.

[0108] (result) The results of the antimicrobial activity tests of the examples against Staphylococcus aureus and Escherichia coli are shown in Tables 3 and 4, respectively. Antimicrobial activity was confirmed for all tested examples, albeit to varying degrees. The size of the halo is known to depend on the water solubility of the sample, and these results are considered to be in line with the water solubility of the examples.

[0109] [Table 3]

[0110] [Table 4]

[0111] (Test Example 2: Mold Resistance Test of Composition) For the mold resistance test, the test method specified in JIS Z 2911 was used as a reference, with paper discs containing the examples used as samples. The molds used in the test were Aspergillus niger and Chaetomium globosum.

[0112] An aqueous solution was prepared by removing the agar from an inorganic salt agar medium (0.7 g potassium dihydrogen phosphate, 2.0 g sodium nitrate, 0.5 g potassium chloride, 0.3 g dipotassium hydrogen phosphate, 0.01 g iron(II) sulfate heptahydrate, 0.5 g magnesium sulfate heptahydrate, 1000 mL distilled water, and 20 g agar). Spores of the mold to be used for the test were added to the aqueous solution, and the concentration was adjusted to 10⁶ ± 200,000 spores / mL. This solution was then mixed in an equivalent volume with a wetted solution (0.05 g / L sodium lauryl sulfate aqueous solution) to prepare the bacterial inoculum.

[0113] The examples were diluted with DMSO or ethanol to prepare test solutions. Paper discs with a diameter of 8 mm were immersed in this solution and air-dried on filter paper for 24 hours to prepare test specimens. After sterilizing inorganic salt agar plates, they were dispensed into petri dishes, allowed to solidify, and then the inoculum was spread on them using a platinum loop. The test specimens were placed on top of this and incubated at 28-30°C for 14-28 days.

[0114] After culturing, the test specimens were observed with the naked eye and under a microscope (40x magnification) to examine the degree of bacterial growth. The degree of growth was expressed numerically as follows: 0: No bacterial growth at all on the sample surface, 1: Bacterial growth can be confirmed on the sample surface under a microscope, 2: Growth of less than 25% of the sample surface area, 3: Growth of 25% or more but less than 50% of the sample surface area, 4: Growth of 50% or more of the sample surface area, 5: Bacteria cover the entire surface of the sample.

[0115] Furthermore, to confirm mold resistance under actual environmental conditions, a mold resistance test was conducted as described above using a microbial sample containing a mixture of five types of mold (Aspergillus niger, Chaetomium globosum, Penicillium citrinum, Rhizopus oryzae, and Cladosporium sphaerospermum).

[0116] (result) The results of mold resistance tests against Aspergillus niger and Chaetomium globosum are shown in Tables 5 and 6, respectively. TBZ is known to exhibit good mold resistance against both Aspergillus niger and Chaetomium globosum. In fact, mold resistance tests of compositions containing TBZ confirmed clear mold resistance against both fungi.

[0117] [Table 5]

[0118] [Table 6]

[0119] Table 7 shows the results of mold resistance tests using five types of mold. Looking at the results for Examples 1-1, 1-2, 4-2, 5, and 9, which contain TBZ, the highly hydrophilic Examples 4-2 and 9 show clearer mold resistance compared to the more hydrophobic Examples 5, 1-1, and 1-2. This result supports the idea that the composition is gradually decomposed by carbon dioxide produced when carbon dioxide dissolves in the water in the culture medium, thereby exhibiting antibacterial and antifungal properties.

[0120] In Example 10, which included OPP as an antifungal agent, clear mold resistance was confirmed, similar to that of TBZ. On the other hand, no mold resistance was confirmed in Example 2, which included PT, but mold resistance was improved in Example 3, which combined it with TBZ.

[0121] [Table 7]

[0122] (Test Example 3: Bioactivity Test of the Composition) A commercially available paint (clear coat for iron parts, JAN 4970925-525697: containing acrylic resin, nitrocellulose, and organic solvent, manufactured by Asahi Paint Co., Ltd.) containing 1-5% (mass%) of Example 5 or Example 6 was applied to a 5cm square plastic piece. After drying for 24 hours, the piece was prepared as a test specimen. The test specimen was washed with distilled water, left in water for 24 hours, and then dried. Antimicrobial testing (JIS Z 2801:2000 method), mold resistance testing (JIS Z 2911 method), and antiviral testing (ISO 21702 method) were then performed. Viral infectivity titers were tested using the plaque assay method.

[0123] For antibacterial testing, Staphylococcus aureus and Escherichia coli were used. For mold resistance testing, the same five types of mold as in Test Example 2 were used, and the degree of growth of the test fungi was evaluated in the same manner as in Test Example 2. For antiviral testing, influenza virus and feline calicivirus were used.

[0124] (result) Table 8 shows the antibacterial activity of the paint containing Example 5 against Staphylococcus aureus. Table 9 shows the antibacterial activity of the paint containing Example 5 against Escherichia coli. The following antibacterial activity values ​​are the logarithm of the ratio of the number of viable bacteria immediately after inoculation to the number of viable bacteria after 24 hours, and a value of 2.0 or higher indicates sufficient antibacterial activity.

[0125] [Table 8]

[0126] [Table 9]

[0127] Table 10 shows the antibacterial activity of the paint containing Example 6 against Staphylococcus aureus. Table 11 shows the antibacterial activity of the paint containing Example 6 against Escherichia coli.

[0128] [Table 10]

[0129] [Table 11]

[0130] Table 12 shows the antifungal properties of the paint containing Example 5. Table 13 shows the antifungal properties of the paint containing Example 6. Examples 5 and 6 showed concentration-dependent antifungal properties.

[0131] [Table 12]

[0132] [Table 13]

[0133] Table 14 shows the antiviral activity of the paint containing Example 6 against influenza virus. Table 15 shows the antiviral activity of the paint containing Example 6 against feline calicivirus. Note that the following antiviral activity is the logarithm of the ratio of the viral infectivity titer after 24 hours to the viral infectivity titer of the blank test, i.e., Sample 1, and a value of 2.0 or higher indicates sufficient antiviral activity.

[0134] [Table 14]

[0135] [Table 15]

[0136] In this test, it was shown that Examples 5 and 6 possess antibacterial, mold-resistant, and antiviral properties even when added to paint.

[0137] The embodiments described above are for illustrative purposes only and do not limit the scope of the present invention. That is, the scope of the present invention is defined not by the embodiments, but by the claims. Various modifications made within the scope of the claims and equivalent inventive meaning are considered to be within the scope of the present invention. [Industrial applicability]

[0138] The present invention is useful for coatings having antibacterial, antifungal, and antiviral activity.

Claims

1. Polyhexamethylene biguanide and A compound that is at least one selected from the group consisting of thiabendazole, orthophenylphenol, and 2-mercaptopyridine-N-oxide, Includes, The polyhexamethylene biguanide and the compound are ionically bonded to form nanoparticles with a particle size of 1 to 1000 nm. Nanoparticle composition.

2. It also contains acidic components, The nanoparticle composition according to claim 1.

3. The acid dissociation constant pKa of the aforementioned acidic component is: It is 10 or less. The nanoparticle composition according to claim 2.

4. The aforementioned acidic component is It is at least one selected from the group consisting of hydrochloric acid, benzoic acid, oleic acid, lauric acid, lactic acid, and acetic acid. The nanoparticle composition according to claim 2 or 3.

5. A nanoparticle composition comprising the nanoparticle composition according to any one of claims 1 to 4, Antibacterial, antifungal, and antiviral agent.

6. A nanoparticle composition comprising the nanoparticle composition according to any one of claims 1 to 4, Antibacterial, antifungal, and antiviral paint.

7. The nanoparticle composition according to claim 1, The acidic component to be mixed with the aforementioned nanoparticle composition, A kit for preparing antibacterial, antifungal, and antiviral agents.

8. A mixing step comprising mixing polyhexamethylene biguanide and a compound selected from the group consisting of thiabendazole, orthophenylphenol, and 2-mercaptopyridine-N-oxide under alkaline conditions, thereby forming nanoparticles having a particle size of 1 to 1000 nm through ionic bonding between the polyhexamethylene biguanide and the compound. A method for producing a nanoparticle composition.

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