JP7190132B2 - Zinc-containing antibacterial agent - Google Patents

Description

The present invention relates to zinc-containing antibacterial agents. More specifically, biomaterials, detergents, cosmetics, paints, resins, wood preservatives, cement admixtures, water treatment agents, industrial water, pulp and paper, plastics, fibers, food additives, medical equipment, optical equipment, modules. , to zinc-containing antibacterial agents useful in electronic products and the like.

Since infectious diseases caused by bacteria such as O157 threaten human life, countermeasures against bacteria and the like are required worldwide. In recent years, in Japan, various antibacterial processed products have been marketed not only in the medical and sanitary fields but also in various fields due to consumers' preference for cleanliness. Antibacterial agents used in antibacterial processing can be classified into organic agents and inorganic agents. For example, the proportion of inorganic agents used in the field of daily necessities is increasing. For example, Non-Patent Document 1 describes the classification and antibacterial mechanism of inorganic antibacterial agents, and discloses the antibacterial performance of various metal ions. In addition, regarding those using silver as an antibacterial component, Patent Document 1 discloses a sparingly soluble antibacterial component of two or more metals selected from the group consisting of magnesium, calcium, strontium, manganese, nickel, copper, and zinc. An antibacterial/antifungal double salt of phosphoric acid is disclosed, which is characterized by supporting 0.1 to 5.0% by weight of silver on a double salt of orthophosphoric acid.

JP-A-05-294808

Noriyuki Yamamoto, “Inorganic Materials” (Japan), 1999, Vol. 6, p468-473

As described above, various antibacterial agents have been disclosed in the past, and Patent Document 1 discloses a technique using silver as an antibacterial component. In addition, Non-Patent Document 1 discloses various metal elements as antibacterial components. Among metals, zinc is known to be relatively safe, and Non-Patent Document 1 discloses zinc oxide. Thus, there was room for developing additional antibacterial agents using zinc.

The present invention has been made in view of the above-mentioned current situation, and an object of the present invention is to provide an antibacterial agent containing elemental zinc having excellent antibacterial properties.

The present inventors conducted various studies on compounds containing elemental zinc, and found that a double salt containing elemental zinc, an alkali metal element, and an oxoacid-derived component has excellent antibacterial properties. The present invention has been arrived at by conceiving that it is possible.

That is, the present invention is a zinc-containing antibacterial agent containing a double salt containing a zinc element, an alkali metal element and an oxoacid-derived component.

The oxoacid-derived component is preferably a phosphoric acid-derived component.

The above double salt has the following formula (1);
_MxHy ( _{ZnPO4 ) z.mH2O} ( ₁ )
(In the formula, M represents an alkali metal element. x represents a number greater than 0. y represents a number of 0 or more. z represents a number of 1 to 10. However, x, y and z satisfies x+y=z, and m represents a number from 0 to 16.).

The present invention is also a zinc-containing antibacterial agent composition containing the above-mentioned zinc-containing antibacterial agent and components other than the above-mentioned zinc-containing antibacterial agent.

The zinc-containing antibacterial agent of the present invention has the above structure and is excellent in antibacterial properties, so it can be used as detergents, cosmetics, paints, resins, wood preservatives, cement admixtures, water treatment agents, industrial water, paper pulp, plastics. , fibers, food additives, biomaterials, medical equipment, optical equipment, modules, electronic products and the like.

2 is a chart showing XRD measurement results of the zinc-containing antibacterial agent obtained in Example 1. FIG. 1 is an SEM photograph of the zinc-containing antibacterial agent obtained in Example 1 (magnification: 2000 times). 1 is a graph showing the results of antibacterial property evaluation (1) for the zinc-containing antibacterial agent obtained in Example 1 and zinc oxide as Comparative Example 1. FIG. 2 is a graph showing the results of antibacterial property evaluation (2) for the zinc-containing antibacterial agent obtained in Example 1 and zinc oxide as Comparative Example 1. FIG. 4 is a chart showing XRD measurement results of the antibacterial material (1) of Example 2. FIG. 4 is a chart showing XRD measurement results of the antibacterial material (2) of Example 3. FIG. 4 is a chart showing XRD measurement results of comparative antibacterial material (1) of Comparative Example 1. FIG. 2 is a graph showing the results of antibacterial property evaluation (3) for the antibacterial material (1) obtained in Example 2 and the comparative antibacterial material (1) obtained in Comparative Example 2. FIG.

Preferred embodiments of the present invention will be specifically described below, but the present invention is not limited to the following description, and can be appropriately modified and applied without changing the gist of the present invention. In addition, the form which combined 2 or 3 or more of each preferable form of this invention described below also corresponds to the preferable form of this invention.

<Zinc-containing antibacterial agent>
The zinc-containing antibacterial agent of the present invention contains a double salt containing a zinc element, an alkali metal element, and an oxoacid-derived component.
The antibacterial agent in the present invention means an agent having antibacterial properties. Antibacterial performance refers to the performance of sterilization (killing microorganisms), bacteriostasis (suppressing the growth of microorganisms), sterilization, disinfection, antibacterial, sterilization, antiseptic, antifungal, etc. The target microorganisms are , bacteria and fungi.

Target microorganisms are not particularly limited, but specific examples include S. mutans, S. sobrinus, Lactobacillus, P. gingivalis, T. forsythia, P. intermedia, T. denticola, A. actinomycetemcomitans, A. naeslundii, E. corrodens, Spirochetes, Fusobacterium, and C. albicans.

Alkali metal elements in the double salt contained in the zinc-containing antibacterial agent of the present invention are not particularly limited, and include lithium, sodium, potassium, rubidium, cesium, and francium. As the alkali metal element, one of these may be used, or two or more may be used. Preferred alkali metal elements are lithium, sodium and potassium, more preferred are sodium and potassium, and still more preferred is sodium.

The double salt may contain an oxoacid-derived component, but the double salt preferably has an oxoacid-derived anion structure.
The oxoacid is not particularly limited as long as it is a compound in which a hydroxyl group and an oxo group are bonded to the central atom and the hydroxyl group gives an acidic proton. Examples of the central atom include carbon atom, sulfur atom, phosphorus atom, nitrogen atom, boron atom and silicon atom; halogen atoms such as fluorine, chlorine, bromine and iodine; transition metal atoms such as chromium and manganese; A phosphorus atom, a sulfur atom, a carbon atom and a nitrogen atom are preferred, and a phosphorus atom is more preferred.
Examples of the oxoacid include phosphoric acid, phosphorous acid, pyrophosphoric acid, carbonic acid, orthocarbonic acid, carboxylic acid, silicic acid, nitrous acid, nitric acid, arsenic acid, sulfurous acid, sulfuric acid, sulfonic acid, sulfinic acid, chromic acid, and dichromic acid. acid, permanganic acid, and the like. Preferred are phosphoric acid, phosphorous acid and pyrophosphoric acid, and more preferred is phosphoric acid.
That is, the form in which the oxoacid-derived component is a phosphoric acid-derived component is one of the preferred embodiments of the present invention.

The cations and anions contained in the double salt are not particularly limited as long as the above double salt contains a zinc element, an alkali metal element, and an oxoacid-derived component, and ions composed of components other than the above three components are included. may contain.
Examples of ions composed of elements or components other than zinc elements, alkali metal elements, and oxoacid-derived components include hydrogen ions and alkaline earth metal ions.
The double salt preferably contains an anion containing a zinc element and an oxoacid-derived component, and an alkali metal ion.

The above double salt has the following formula (1);
_MxHy ( _{ZnPO4 ) z.mH2O} ( ₁ )
(In the formula, M represents an alkali metal element. x represents a number greater than 0. y represents a number of 0 or more. z represents a number of 1 to 10. However, x, y and z satisfies x+y=z, and m represents a number from 0 to 16.).
It should be noted that each composition ratio in the composition formula of a compound or the like is generally represented by the smallest integer ratio, but the structure represented by the composition ratio represented by the smallest integer ratio is the unit structure in the crystal structure. In the present invention, compounds having such a crystal structure, which may not exist in some cases, are represented by the minimum integer ratio in the above formula (1). Therefore, the above formula (1) does not necessarily represent the actual unit structure of the double salt.
x is preferably 1 to 10, more preferably 1 to 6.
y is preferably 0 to 5, more preferably 0 to 3, and most preferably 0.
z is preferably 1 to 8, more preferably 1 to 6.
m is preferably 0 to 12, more preferably 0 to 8.
The combination of x, y, z, m is preferably (x, y, z, m) = (3, 0, 3, 4), (1, 0, 1, 1), more preferably ( x,y,z,m)=(3,0,3,4).

More preferably, the double salt is represented by the following formula (2);
M6( _ZnPO4 ) _{6.8H2O ( 2} )
(In the formula, M represents an alkali metal element). In the double salt represented by the above formula (2), the structure represented by the formula (2) is the minimum unit structure (unit cell) instead of water molecules entering the crystal as hydration water. Since it has a crystal structure, the composition ratio in the formula (2) is not the minimum integer ratio, but the composition ratio of the actual unit cell.
Na ₆ (ZnPO ₄ ) _{6.8H 2} O is most preferable as the double salt.

The method for producing the double salt contained in the zinc-containing antibacterial agent of the present invention is not particularly limited, but preferably includes a step of reacting a zinc element-containing compound, an alkali metal element-containing compound, and an oxoacid.
In the reaction step, the method of reacting the above components is not particularly limited, but a basic salt is added to a solution containing a zinc element-containing compound, an alkali metal element-containing compound, and an oxoacid to precipitate a double salt. A method is preferred.
The basic salt is not particularly limited as long as it exhibits basicity when dissolved in water. be done. Alkali metal hydroxides are preferred, and sodium hydroxide and potassium hydroxide are more preferred.

The zinc element-containing compound is not particularly limited as long as it contains zinc element, and examples thereof include zinc complexes and zinc-containing salts. The anion that forms a salt with zinc is not particularly limited, but nitrate ion, nitrite ion, sulfate ion, sulfite ion, hydrogen sulfite ion, acetate ion, carbonate ion, hydrogen carbonate ion, phosphate ion, silicate ion, borate ions, halogen ions, hydroxide ions, and the like. Preferred are nitrate ions, nitrite ions, sulfate ions, sulfite ions, hydrogen sulfite ions, and acetate ions. As the zinc-containing salt, zinc acetate, zinc sulfate, zinc nitrate, zinc phosphate and the like are preferable, and zinc nitrate and zinc acetate are more preferable.

The alkali metal element-containing compound is not particularly limited as long as it contains an alkali metal element, but a salt containing an alkali metal is preferable. Preferred forms of the alkali metal element are as described above.
The anion that forms a salt with an alkali metal is not particularly limited, and includes the anions described above. Halogen ions, carbonate ions, hydrogen carbonate ions, and hydroxide ions are preferred. Preferred halogen ions are fluoride ion, chloride ion, bromide ion and iodide ion, and more preferred are chloride ion and bromide ion. The alkali metal element-containing salt is preferably an alkali metal halide, more preferably sodium chloride or sodium bromide.

Specific examples of the oxoacid are as described above, preferably phosphoric acid, phosphorous acid, and pyrophosphoric acid.

The ratio (mol%) of the amount of the zinc element-containing compound, the alkali metal element-containing compound, and the oxoacid used in the method for producing a double salt (zinc element-containing compound/alkali metal element-containing compound/oxoacid) is 10 to 50/ It is preferably 10-50/20-60. It is more preferably 20-40/20-40/30-50.

The amount of the basic salt to be used in the method for producing the double salt is not particularly limited, but is preferably 100 to 500 mol % with respect to 100 mol % of the zinc element-containing compound. More preferably 200 to 400 mol %.

<Zinc-containing antibacterial agent composition>
A zinc-containing antibacterial agent composition (hereinafter also referred to as an antibacterial agent composition) containing the zinc-containing antibacterial agent of the present invention and other components other than the zinc-containing antibacterial agent is also one aspect of the present invention.
The content of the zinc-containing antibacterial agent in the antibacterial agent composition is preferably 0.01 to 50% by weight with respect to 100% by weight of the antibacterial agent composition. More preferably 0.05 to 30% by mass, still more preferably 0.1 to 20% by mass.
The above-mentioned other components are not particularly limited as long as they do not inhibit the antibacterial performance of the zinc-containing antibacterial agent, and examples thereof include solvents, thickeners, binders, and the like.
From the viewpoint of improving antibacterial properties, the antibacterial agent composition contains metal salts, metal oxides, metal hydroxides, etc. other than the double salt containing the zinc element, the alkali metal element, and the oxoacid-derived component. good too. As the metal in the metal salts, oxides, and metal hydroxides, transition metals such as copper, silver, and titanium are preferred.

Examples of the solvent include water; amides such as N-methyl-2-pyrrolidone, N,N'-dimethylformamide and N,N'-dimethylacetamide; polar solvents such as alcohols such as methanol, ethanol and isopropyl alcohol; is mentioned. Among them, water is preferred.

<Antimicrobial material>
The present invention is also an antimicrobial material comprising the zinc-containing antimicrobial agent or zinc-containing antimicrobial composition of the present invention and a substrate.
By using the zinc-containing antibacterial agent or zinc-containing antibacterial agent composition of the present invention supported on a substrate, the antibacterial performance can be exhibited more effectively.

The substrate is not particularly limited as long as it can support the zinc-containing antibacterial agent or the zinc-containing antibacterial agent composition, and is paper, fiber substrate, wood, resin foam, porous substrate, film substrate. , particulate substrates, and the like.
Examples of the fiber base material include woven fabrics such as gauze, knitted fabrics, braids, laces, nets, and non-woven fabrics.
Examples of the resin foam include, but are not particularly limited to, foamed polyurethane, foamed polystyrene, and the like.

The material constituting the base material is not particularly limited and may be appropriately selected depending on the application. Examples include collagen, gelatin, fibrin, chitosan, hyaluronic acid, polylactic acid; animal fibers such as silk and wool; polyester. , polypropylene; cellulosic fibers such as cotton, hemp, rayon, cupra, lyocell, polynosic, acetate and triacetate; polymer materials such as hydroxyapatite and inorganic materials such as calcium triphosphate.
As a material constituting the base material, only one of these may be used, or two or more of them may be used in combination.
At least one material selected from the group consisting of collagen, gelatin, fibrin, chitosan, hyaluronic acid, polylactic acid, hydroxyapatite, and calcium triphosphate is preferable as the material constituting the base material. Collagen is more preferred.

The base material is preferably a fiber base material or a porous base material, more preferably a porous base material, and still more preferably a scaffold that functions as a scaffold for regeneration of cells, tissues, and the like. Among them, a collagen scaffold containing collagen as a main component is preferred.

The base material may contain components other than the above materials, and may contain, for example, an osmotic pressure adjusting substance, a pH buffering agent, and the like. Examples of components contained in these include alkali metal components, halogen components, and oxoacid-derived components such as oxoacids and anions derived from oxoacids.
When the base material contains the alkali metal component and the oxoacid-derived component, a double salt containing the zinc element, the alkali metal element, and the oxoacid-derived component in the antibacterial material is obtained by adding the zinc element-containing compound to the base material. may be formed.

The content of zinc element in the antibacterial material is preferably 0.01 to 1% by mass with respect to 100% by mass of the antibacterial material. More preferably, it is 0.05 to 0.5% by mass.
The content of the alkali metal element in the antibacterial material is preferably 0.005 to 2% by mass with respect to 100% by mass of the antibacterial material. More preferably, it is 0.02 to 1% by mass.
The content of phosphorus element in the antibacterial material is preferably 0.005 to 2% by mass with respect to 100% by mass of the antibacterial material. More preferably, it is 0.03 to 1% by mass.
The content of these elements can be measured by X-ray fluorescence (XRF) analysis described in Examples.

The zinc-containing antibacterial agent, the zinc-containing antibacterial agent composition, and the antibacterial material of the present invention are composed of the above-described structure and have excellent antibacterial performance, so they are used for tissue regeneration such as bones and skin. Softening agents, household detergents, dishwashing agents, cleaning agents for hard surfaces, etc.; shampoos, rinses, lotions, milky lotions, creams, sunscreens, foundations, eye makeup products, antiperspirants, etc. Cosmetic applications; industrial applications such as paints, wood preservatives, cement admixtures, industrial water (papermaking process water in the papermaking process, cooling water and washing water for various industries); masks, eye patches, bandages, plasters, gauze, etc. Sanitary goods; medical instruments; textile products such as clothing; food additives;

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited only to these examples. Unless otherwise specified, "part" means "mass part" and "%" means "mass %".

Various physical properties were measured by the following methods.
<Measurement of X-ray fluorescence (XRF)>
The XRF measurement was performed using a fluorescent X-ray analyzer (ZSX Primus2, manufactured by Rigaku Corporation) and an Rh (4 kW) X-ray tube, using a calibration curve method.

<Measurement of X-ray diffraction (XRD)>
The XRD measurement was performed under the following conditions using a fully automatic horizontal X-ray diffractometer (SMART LAB manufactured by Rigaku Corporation).
CuKα1 line: 0.15406 nm
Scan range: 10°-90°
X-ray output setting: 45kV-200mA
Step size: 0.020°
Scanning speed: 0.5°min ^-1 -4°min ^-1
The XRD measurement was performed in a state in which an inert atmosphere was maintained by loading the sample onto an airtight sample table in a glove box.

<SEM Observation>
SEM observation was performed using a scanning electron microscope (manufactured by JEOL Ltd., JSM-7600F) with accelerated electrons of 5.0 keV, and a backscattered electron image was observed.

<Antibacterial evaluation (1)>
A suspension of Actinomyces naeslundii (ATCC 27039) (4.4 × 10 ⁷ CFU/well) was seeded in a 48-well plate, and a zinc-containing antibacterial agent dispersion diluted with distilled water (final concentration 0.1 wt%, 0.01 wt. %) and zinc oxide (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) dispersion (final concentration 0.04 wt%, 0.004 wt%) 100 μL were added, respectively, and anaerobic culture was performed at 37 ° C. for 24 hours. was measured. A smaller turbidity indicates a higher antimicrobial activity. As a control, the same test was conducted using distilled water instead of the zinc-containing antibacterial agent dispersion.

<Antibacterial evaluation (2)>
A zinc-containing antibacterial agent dispersion (10 wt%) diluted with distilled water and a zinc oxide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) dispersion (4 wt%) 100 μL are dropped onto a 48-well plate, dried at room temperature and tested. A coating was created. 0.5 mL of a suspension of Actinomyces naeslundii (ATCC 27039) (5.5×10 ⁷ CFU/well) was inoculated on the membrane and cultured anaerobically at 37° C. for 24 hours, and then the turbidity of the medium was measured. A smaller turbidity indicates a higher antimicrobial activity. As a control, a similar test was conducted on a sample without a test film.

<Antibacterial evaluation (3)>
The prepared sample was placed in a 48-well plate, a suspension of Streptococcus mutans (ATCC 35668) (6.0×10 ⁶ CFU/well) was seeded, and anaerobically cultured at 37° C. for 24 hours. was measured. A smaller turbidity indicates a higher antimicrobial activity. As a control, a similar test was conducted without using a sample.

<Example 1> Preparation of zinc-containing antibacterial agent A zinc-containing antibacterial agent (Na ₆ (ZnPO ₄ ) _{6.8H 2} O) was synthesized with reference to the non-patent literature (Nature, 349, (1991) 508-511). did. Zinc nitrate hexahydrate (7.14 g, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), sodium bromide (2.06 g, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) and, 80% phosphoric acid (3.68 g, manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was dissolved using a magnetic stirrer. When an 8% sodium hydroxide solution (42 g, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) prepared from solid sodium hydroxide and ion-exchanged water was added at once, a reaction occurred and a gel-like white solid precipitated. Further vigorous stirring yielded a homogeneous white dispersion. After stirring as it was for 2 hours, the stirring was stopped and the mixture was allowed to stand overnight. After standing, filtration and washing with deionized water were repeated to obtain a white solid. The solid was dried by vacuum drying at room temperature to obtain a zinc-containing antibacterial agent (4.9 g of white powder).

The zinc-containing antibacterial agent obtained in Example 1 was subjected to XRD measurement. The results are shown in FIG. From FIG. 1, it became clear that the zinc-containing antibacterial agent was a _double salt represented by _Na6 ( _ZnPO4 ) _6.8H2O .
The zinc-containing antibacterial agent obtained in Example 1 was observed by SEM. The results are shown in FIG.
From FIG. 2, it was confirmed that the particles (double salt) contained in the zinc-containing antibacterial agent were particles with relatively uniform shapes and particle sizes.

The zinc-containing antibacterial agent obtained in Example 1 and zinc oxide as Comparative Example 1 were evaluated for antibacterial properties (1). The results are shown in FIG.

The zinc-containing antibacterial agent obtained in Example 1 and zinc oxide as Comparative Example 1 were evaluated for antibacterial properties (2). The results are shown in FIG.

<Example 2> Preparation of antibacterial material (1) A scaffold (Terdermis (registered trademark), Olympus Termo Biomaterial) (hereinafter also referred to as Ter) molded to 6 x 6 x 3 mm was coated with zinc acetate (hereinafter referred to as Zn.) It was immersed in 0.1 mL of a 0.01% by mass N-methylpyrrolidone solution, washed with ethanol, and dried to obtain an antibacterial material (1).

<Example 3> Preparation of antibacterial material (2) Antibacterial material (2) was obtained in the same manner as in Example 2, except that the concentration of zinc acetate was changed to 0.1% by mass.

<Comparative Example 2> Preparation of Comparative Antibacterial Material (1) Comparative antibacterial material was prepared in the same manner as in Example 2, except that N-methylpyrrolidone was used instead of the 0.01 mass% zinc acetate N-methylpyrrolidone solution. (1) was obtained.

The antibacterial material (1) obtained in Example 2 and the comparative antibacterial material (1) obtained in Comparative Example 2 were subjected to XRF measurement. Table 1 shows the results.

From Table 1, it is clear that the antibacterial material (1) carries zinc.

The antibacterial materials (1) and (2) obtained in Examples 2 and 3 and the comparative antibacterial material (1) obtained in Comparative Example 2 were subjected to XRD measurement. The results are shown in Figures 5-7.
5 and ₆ , a peak derived from the structure represented by Na ₆ (ZnPO ₄ ) 6.8H ₂ O was observed, and the antibacterial materials (1) and (2) contained Na ₆ (ZnPO ₄ ) ₆ . It was found to contain a double salt represented by 8H ₂ O.

Antibacterial property evaluation (3) was performed on the antibacterial material (1) obtained in Example 2 and the comparative antibacterial material (1) obtained in Comparative Example 2. The results are shown in FIG.
The results of FIG. 8 demonstrate that the antibacterial material (1) containing the double salt of the present invention is superior in antibacterial performance to the comparative antibacterial material (1) that does not contain the double salt.

Claims (4)

containing a double salt containing a zinc element, an alkali metal element, and an anion having a hydroxyl group and an oxo group bonded to the central atom ;
A zinc-containing antibacterial agent , wherein the central atom in the anion is at least one selected from the group consisting of a carbon atom, a sulfur atom, a phosphorus atom, a nitrogen atom, a boron atom, a halogen atom, chromium, and manganese . (However, those containing aluminum or silicon elements are excluded.) 2. The zinc-containing antibacterial agent according to claim 1, wherein said anion is a phosphate anion . The double salt has the following formula (1);
_MxHy ( _{ZnPO4 ) z.mH2O} ( ₁ )
(In the formula, M represents an alkali metal element. x represents a number greater than 0. y represents a number of 0 or more. z represents a number of 1 to 10. However, x, y and 3. The zinc-containing antibacterial agent according to claim 1, wherein z satisfies x+y=z, and m represents a number from 0 to 16. A zinc-containing antibacterial agent composition comprising the zinc-containing antibacterial agent according to any one of claims 1 to 3 and components other than the zinc-containing antibacterial agent.

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