Microbial flora improving agent

Abstract

To provide a microbial flora improving agent for improving microbial flora of a mucosa and / or a nail, which is highly effective in suppressing pathogenic bacteria while preserving non-pathogenic indigenous bacteria, which enables sustained improvement of microbial flora balance, and which can maintain the above effects over a long period of time.SOLUTION: A microbial flora improving agent comprises: a substance (X) which is at least one selected from the group consisting of: a compound (X1) having two or more hydroxy groups included in an oxo acid group and salts thereof; a compound (X2) having one hydroxy group included in an oxo acid group and salts thereof; a heterocyclic compound (X3) having no oxo acid group and salts thereof; and a ketone (X4) having no oxo acid group; a polymer (Y); and a preservative (Z).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a bacterial flora improving agent. [Background technology]

[0002] Various types of bacteria coexist in the human body (mucous membranes (in the mouth, etc.), nails, etc.), forming a bacterial community called the bacterial flora. This flora is a mixture of so-called non-pathogenic resident bacteria and pathogenic bacteria. Normally, the balance of the bacterial flora is maintained, which is known as a healthy state, and diseases caused by pathogenic bacteria are suppressed.

[0003] However, if the balance of the bacterial flora is disrupted due to diet, antibiotic intake, stress, aging, poor cleaning, etc., pathogenic pathogenic bacteria and opportunistic infectious bacteria will increase, leading to disease. Therefore, in order to control disease, it is important not only to suppress pathogenic bacteria, but also to maintain a healthy balance of the bacterial flora with non-pathogenic resident bacteria.

[0004] Incidentally, there are known techniques relating to inhibitors of virulence factor production that exhibit a function of acting on specific harmful bacteria, such as the technique described in Patent Document 1. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 5716173 Summary of the Invention [Problem to be solved by the invention]

[0006] However, as a result of investigation, it was found that when the pathogenicity factor production inhibitor described in Patent Document 1 is used as is, it not only suppresses the action of pathogenic bacteria, but also has a significant adverse effect on non-pathogenic resident bacteria, and it is difficult to sustainably suppress the action of pathogenic bacteria at the application site, and therefore a means of improvement is needed to maintain the balance of the bacterial flora in a sustained healthy state.

[0007] Therefore, an object of the present invention is to provide a bacterial flora improver for improving the bacterial flora of mucosa and / or nails, which exhibits a high inhibitory effect on pathogenic bacteria while maintaining non-pathogenic resident bacteria, can continuously improve the balance of the bacterial flora, and can maintain the above-mentioned effect for a long period of time. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems, and have arrived at the present invention. That is, the present invention relates to a compound (X1) having two or more hydroxy groups in an oxo acid group and a salt thereof, Compound (X2) having one hydroxy group contained in an oxo acid group and a salt thereof, A heterocyclic compound (X3) having no oxoacid group and a salt thereof, A substance (X) which is at least one selected from the group consisting of ketones (X4) having no oxo acid group; A polymer (Y); A bacterial flora improver comprising a preservative (Z), The compound (X1), the compound (X2), the heterocyclic compound (X3) and the ketone (X4) do not have an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms, the total mass ratio of the oxo acid groups, the hydroxy groups not contained in the oxo acid groups, the carbonyl groups not contained in the oxo acid groups, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton contained in the compound (X1) is 45 mass% or more based on the molecular weight of the compound (X1); the compound (X2) has an atom having an unshared electron pair (excluding atoms contained in an oxoacid group, and atoms contained in an amino group not constituting an imidazole skeleton and an amino group not constituting a pyridine skeleton), the total mass ratio of the oxo acid groups, the hydroxy groups not contained in the oxo acid groups, the carbonyl groups not contained in the oxo acid groups, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton contained in the compound (X2) is 55 mass% or more based on the molecular weight of the compound (X2); the heterocyclic compound (X3) has an imidazole skeleton or a pyridine skeleton and a hydroxy group and / or a carbonyl group, or has two or more skeletons selected from an imidazole skeleton and a pyridine skeleton, the total mass ratio of carbon atoms contained in the imidazole skeleton and the pyridine skeleton, nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton, hydroxy groups, and carbonyl groups contained in the imidazole skeleton and the pyridine skeleton of the heterocyclic compound (X3) is 50 mass% or more based on the molecular weight of the heterocyclic compound (X3); The ketone (X4) has a linear β-diketone structure, the total weight ratio of the hydroxyl groups and the carbonyl groups in the ketone (X4) is 30 mass% or more based on the molecular weight of the compound (X4); The formula weight of the substance (X) is 550 or less, The polymer (Y) has an HLB value of 7 or more and a weight average molecular weight of 10,000 to 3,000,000; the preservative (Z) is at least one selected from the group consisting of benzoic acid and its salts, paraoxybenzoic acid esters, phenoxyethanol, 1,2-pentanediol, and isopropylmethylphenol; the bacterial flora improver does not contain an anionic surfactant (S) or contains 2% by weight or less of an anionic surfactant (S) based on the total weight of the substance (X); the anionic surfactant (S) has an anionic group and a chain aliphatic hydrocarbon group having 12 to 30 carbon atoms which may be substituted, The chemical formula weight or weight average molecular weight of the anionic surfactant (S) is 1000 or less. A bacterial flora improving agent for improving the bacterial flora of mucous membranes and / or nails. Effect of the Invention

[0009] According to the present invention, it is possible to provide a bacterial flora improver for improving the bacterial flora of mucosa and / or nail, which exhibits a high inhibitory effect on pathogenic bacteria while maintaining non-pathogenic resident bacteria, can continuously improve the balance of bacterial flora, and can maintain the above-mentioned effect for a long period of time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The bacterial flora improver of the present invention for improving the bacterial flora of mucosa and / or nail (hereinafter also referred to as the "microbial flora improver of the present invention") contains at least one substance (X) selected from the group consisting of compounds (X1) having two or more hydroxy groups in an oxo acid group and salts thereof, compounds (X2) having one hydroxy group in an oxo acid group and salts thereof, heterocyclic compounds (X3) having no oxo acid group and salts thereof, and ketones (X4) having no oxo acid group, a polymer (Y), and a preservative (Z).

[0011] The bacterial flora improving agent of the present invention exhibits a high inhibitory effect on pathogenic bacteria while maintaining non-pathogenic resident bacteria, thereby improving the balance of the bacterial flora, and is effective in maintaining the above-mentioned effect for a long period of time. In addition, the above-mentioned "high pathogenic bacteria suppression effect" means at least one of killing harmful bacteria, inactivating harmful bacteria and suppressing their growth, and suppressing the production of toxic substances (pathogenic factors) of harmful bacteria.

[0012] As used herein, "pathogenic bacteria" refers to bacteria, fungi, and the like that are highly pathogenic and cause various infectious diseases and the like through proliferation, and specific examples thereof include Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, Trichophyton rubrum, Trichophyton mentagrophytes, Candida albicans, Candida glabrata, and the like. Furthermore, the term "non-pathogenic resident bacteria" refers to resident bacteria that have the effect of inhibiting the growth of the above-mentioned pathogenic bacteria and maintaining health, and specific examples thereof include Staphylococcus epidermidis, Streptococcus salivarius, etc.

[0013] Among the above pathogenic bacteria, Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia are known as pathogenic bacteria that can occur in the oral cavity. Among the above pathogenic bacteria, Trichophyton rubrum, Trichophyton mentagrophytes, Staphylococcus aureus, Candida albicans, and Candida glabrata are known as pathogenic bacteria that can occur in the nails. Among the above non-pathogenic bacteria, Streptococcus salivarius is known as a normal inhabitant of the oral cavity. Among the above non-pathogenic bacteria, Staphylococcus epidermidis is known as a normal inhabitant of nails.

[0014] The bacterial flora improver of the present invention can selectively inhibit the quorum sensing mechanism (i.e., the mechanism that produces autoinducers) of pathogenic bacteria, and has a high inhibitory effect on pathogenic bacteria while maintaining non-pathogenic resident bacteria.

[0015] [Substance (X)] The bacterial flora improver of the present invention contains a substance (X). The substance (X) is at least one selected from the group consisting of a compound (X1) having two or more hydroxy groups contained in an oxo acid group and a salt thereof, a compound (X2) having one hydroxy group contained in an oxo acid group and a salt thereof, a heterocyclic compound (X3) having no oxo acid group and a salt thereof, and a ketone (X4) having no oxo acid group. The compound (X1), the compound (X2), the heterocyclic compound (X3) and the ketone (X4) do not have an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms. As the substance (X), two or more kinds of each of the compound (X1), the compound (X2), the heterocyclic compound (X3) and the ketone (X4) may be used. Two or more kinds of each of the salts of the compound (X1), the salts of the compound (X2) and the salts of the compound (X3) may also be used.

[0016] The compound (X1) has two or more hydroxy groups contained in an oxo acid group. The compound (X1) may have two or more oxo acid groups. In the present application, the term "oxo acid group" refers to a group having a structure in which a hydroxy group (-OH) and an oxo group (=O) are bonded to one central atom (such as a carbon atom, a phosphorus atom, a sulfur atom, or a tungsten atom). Two or more hydroxy groups and two or more oxo groups may be contained in one oxo acid group. For example, triphosphate [ka] The oxo acid groups of are -P(=O)(OH) at both ends of the molecule. 2 and the central -P(=O)(OH)-, where the oxo acid groups at both ends contain two hydroxyl groups.

[0017] The total mass ratio of the oxo acid group, the hydroxy group not contained in the oxo acid group, the carbonyl group (C=O) not contained in the oxo acid group, the carbon atom contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atom contained in the imidazole skeleton and the pyridine skeleton, which the compound (X1) has, is 45% by mass or more, preferably 55% by mass or more, based on the molecular weight of the compound (X1), from the viewpoint of the effect of the bacterial flora improver. When the bacterial flora improver contains multiple compounds as the compound (X1), each compound satisfies this condition. In the present application, the mass of the oxo acid group is the total mass of the central atom, the oxo group, and the hydroxy group. For example, malic acid has a molecular weight of 134.1. [ka] In the case of malic acid, it has two carboxy groups (formula weight 45.0) which are oxoacid groups and one hydroxy group (formula weight 17.0) which is not included in the oxoacid groups, so the ratio of the total mass of these groups based on the molecular weight of malic acid is [(45.0×2+17.0×1) / 134.1]×100=80(mass%) It is. Although the compound (X1) has an oxoacid group as an essential group, a hydroxyl group not contained in the oxoacid group, a carbonyl group not contained in the oxoacid group, an imidazole skeleton and a pyridine skeleton are not essential and may be optionally contained.

[0018] In the present application, the term "imidazole skeleton" refers to [ka] (R is a hydrogen atom or a group capable of bonding to imidazole). In addition, the "pyridine skeleton" is [ka] It means a structure represented by the formula: These structures may be contained in a fused ring.

[0019] From the viewpoint of further improving the effect of the bacterial flora improver, the total mass ratio of the oxo acid groups, hydroxy groups not contained in the oxo acid groups, and carbonyl groups not contained in the oxo acid groups contained in the compound (X1) is preferably 45 mass% or more based on the molecular weight of compound (X1).

[0020] Compound (X1) may be polyphosphoric acid, tungstic acid (H 2 WO 4 ), ethylenediaminetetraacetic acid, glutamic acid, iminodiacetic acid, malic acid, citric acid, tartaric acid, adenosine triphosphate, guanosine triphosphate, etc. In the present application, tungstic acid is represented by the following chemical formula: [ka] As shown in the figure, it is considered to be a compound having two hydroxy groups contained in an oxo acid group, and is included in compound (X1).

[0021] From the viewpoint of the effect of the microflora improver, the compound (X1) is 2 It is preferred that the aryl group does not have a " group.

[0022] When compound (X1) is a hydroxycarboxylic acid, the ratio of the number of moles of hydroxy groups to the number of moles of carboxy groups (-COOH) in the hydroxycarboxylic acid (number of moles of -OH / number of moles of -COOH) is preferably 1 / 3 or more, and more preferably 1 / 2 or more, from the viewpoint of the effect of the bacterial flora improver.

[0023] The salt of compound (X1) is not particularly limited, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, etc.; organic acid salts such as acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, propionate, etc.; alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; ammonium salt; salts with organic bases such as triethylamine, triethanolamine, pyridine, etc.; amino acid salts with basic or acidic amino acids such as arginine, glutamic acid, etc. Among these, sodium salts and potassium salts are preferred.

[0024] The compound (X2) has an atom having an unshared electron pair (excluding atoms contained in an oxoacid group, and atoms contained in an amino group not constituting an imidazole skeleton and an amino group not constituting a pyridine skeleton). Preferred examples of the atom having an unshared electron pair include an oxygen atom contained in a carbonyl group, an oxygen atom contained in a hydroxy group (excluding the oxygen atom contained in an oxoacid group), a nitrogen atom contained in an imidazole skeleton, and a nitrogen atom contained in a pyridine skeleton.

[0025] Furthermore, the total mass ratio of the oxo acid groups, hydroxy groups not contained in the oxo acid groups, carbonyl groups not contained in the oxo acid groups, carbon atoms contained in the imidazole skeleton and pyridine skeleton, and nitrogen atoms contained in the imidazole skeleton and pyridine skeleton of compound (X2) is 55 mass% or more based on the molecular weight of compound (X2) from the viewpoint of the effect of the bacterial flora improver. When the bacterial flora improver contains multiple compounds as compound (X2), each compound satisfies this condition. The compound (X2) has an oxoacid group as an essential group, and optionally has a hydroxyl group not contained in the oxoacid group, a carbonyl group not contained in the oxoacid group, an imidazole skeleton, and a pyridine skeleton.

[0026] Examples of the compound (X2) include a compound (X21) having no amino group and a compound (X22) having an amino group. Examples of the compound (X21) not having an amino group include hydroxycarboxylic acids (gluconic acid, glucuronic acid, etc.) and keto acids (levulinic acid, etc.). Examples of the compound (X22) having an amino group include glycylglycine and histidine.

[0027] Examples of the salt of compound (X2) include the same as those explained as the salt of compound (X1), and the preferred examples are also the same.

[0028] The heterocyclic compound (X3) has an imidazole skeleton or a pyridine skeleton and a hydroxy group and / or a carbonyl group, or has two or more skeletons selected from the group consisting of an imidazole skeleton and a pyridine skeleton.

[0029] Examples of the heterocyclic compound (X3) include 8-quinolinol (a compound having one pyridine skeleton and a hydroxy group), and phenanthroline (a compound having two pyridine skeletons). The total mass ratio of the carbon atoms contained in the imidazole skeleton and pyridine skeleton, the nitrogen atoms contained in the imidazole skeleton and pyridine skeleton, the hydroxyl group, and the carbonyl group contained in the imidazole skeleton and pyridine skeleton of the heterocyclic compound (X3) is 50 mass% or more based on the molecular weight of the heterocyclic compound (X3) from the viewpoint of the effect of the bacterial flora improver. When the bacterial flora improver contains multiple compounds as the heterocyclic compound (X3), each compound satisfies this condition.

[0030] Examples of the salt of the heterocyclic compound (X3) include the same as those explained as the salt of the compound (X1).

[0031] The ketone (X4) (excluding those corresponding to the heterocyclic compound (X3)) has a linear β-diketone structure. Examples of the ketone (X4) include benzoylacetone and acetylacetone. From the viewpoint of the effect of the bacterial flora improver, the total mass ratio of the hydroxyl groups and carbonyl groups in the ketone (X4) is 30 mass% or more based on the molecular weight of the ketone (X4). When the bacterial flora improver contains multiple compounds as the ketone (X4), each compound satisfies this condition.

[0032] From the viewpoint of safety, the substance (X) is preferably at least one selected from the group consisting of levulinic acid and its salts, tungstic acid and its salts, benzoylacetone, polyphosphoric acid and its salts, and acetylacetone, more preferably polyphosphoric acid (the number of repeating phosphate units is preferably 2 to 5, more preferably 3 to 5) and its salts, and particularly preferably pentasodium triphosphate.

[0033] From the viewpoint of the effect of the microflora improver, the chemical formula weight of the substance (X) is not more than 550. When the microflora improver contains multiple compounds as the substance (X), the chemical formula weight of each molecule is 550 or less.

[0034] The substance (X) preferably captures 1 g or more of magnesium per 100 g of substance (X) when measured by an ion electrode method. In addition, when the substance (X) is a hydrate, the weight means per 100 g excluding the water of hydration. The above measurements using the ion electrode method were performed at 20°C, pH 7, and 1 mM MgCl 2 The aqueous solution is carried out with 2 mM of substance (X).

[0035] Polymer The bacterial flora improving agent of the present invention contains not only the above-mentioned substance (X) but also a polymer (Y). Note that the substance (X) does not fall under the category of polymer (Y). The HLB value of the polymer (Y) is not less than 7. If the HLB value of the polymer (Y) is less than 7, the spreadability of the bacterial flora improving agent deteriorates when applied to an affected area. From the viewpoint of spreadability, the HLB value of the polymer (Y) is preferably 7 to 60.

[0036] The HLB value is an index showing the balance between hydrophilicity and lipophilicity, and is known as a value calculated according to the Oda method described, for example, in "Introduction to Surfactants" [published by Sanyo Chemical Industries, Ltd. in 2007, written by Takehiko Fujimoto], p. 212, and is not a value calculated according to the Griffin method. The HLB value of the polymer (Y) can be calculated based on the ratio of the organic value to the inorganic value of the compound according to the following formula: HLB = 10 x inorganic value / organic value The organic value and inorganic value for deriving the HLB are calculated by setting the organic value to 20 per carbon atom, and using the values ​​in the table on page 213 of the above-mentioned "Introduction to Surfactants" (the "numerical value" for inorganic groups, or the "inorganic value" for organic and inorganic groups). As an example of calculation, -CH 3 Base: Organic value 20, Inorganic value 0, -CH 2 - Group: organic value 20, inorganic value 0, =CH 2 Group: Organic value 20, Inorganic value 1, =CH-group: organic value 10, inorganic value 1, Benzene ring: organic value 120, inorganic value 15, -O-group: inorganic value 20, -COO-: organic value 20, inorganic value 60, -OH group: inorganic value 100, -COOH group: organic value 20, inorganic value 150 etc. are exemplified. In addition, in the calculation of the HLB value in the present invention, for the following configurations, the following organic values and inorganic values are used. COO - M + : organic value 20, inorganic value 400 (note that "M + " is the counter ion of "COO - " and represents a metal cation or an ammonium cation) Si atom: organic value 0, inorganic value 0 Note that when the polymer (Y) is composed of a plurality of components, a weighted average value based on the weight ratio of each component is used as the HLB value of the polymer (Y).

[0037] From the viewpoint of the effect of the flora improver, the content (weight ratio) of the polymer (Y) is preferably 0.1 to 80% by weight, more preferably 1 to 70% by weight, based on the weight of the flora improver. Also, from the viewpoint of the effect of the flora improver, the content (weight ratio) of the polymer (Y) is preferably 30 to 6,000% by weight, more preferably 50 to 5,000% by weight, based on the weight of the substance (X).

[0038] The polymer (Y) has a weight average molecular weight of 10,000 to 3,000,000. Also, as the compound contained in the polymer (Y), the molecular weight is preferably 500 or more. Note that the weight average molecular weight in this specification can be measured under the following conditions using gel permeation chromatography (GPC). <GPC measurement conditions> [1] Apparatus: Gel permeation chromatography [model number "HLC-8120GPC", manufactured by Tosoh Corporation] [2] Column: "TSKgel G6000PWxl" and "TSKgel G3000PWxl" [both manufactured by Tosoh Corporation] connected in series. [3] Eluent: methanol / water = 30 / 70 (volume ratio) dissolved with 0.5 wt% sodium acetate. [4] Reference substance: polyethylene glycol (hereinafter abbreviated as PEG) [5] Injection conditions: sample concentration 0.25 wt%, column temperature 40°C

[0039] Examples of the monomer in the polymer (Y) include monosaccharides [α-glucose, β-glucose, uronic acids (mannuronic acid, guluronic acid, etc.)], (meth)acrylic monomers [(meth)acrylic monomers having 3 to 10 carbon atoms, such as acrylic acid], (alkyl)alkoxysilanes [dialkyldialkoxysilanes having 4 to 40 carbon atoms, such as diethoxydimethylsilane and dimethoxydimethylsilane], and alkylene oxides [alkylene oxides having 2 to 4 carbon atoms, such as ethylene oxide, propylene oxide, and butylene oxide]. In the present invention, (meth)acrylic means acrylic and / or methacrylic. In the present invention, the (alkyl)alkoxysilane means an alkoxysilane and / or an alkylalkoxysilane. Specific examples of the polymer (Y) include carboxyalkylcellulose and its salts (such as carboxymethylethylcellulose and sodium carboxymethylcellulose), alkylcellulose and its salts (such as methylcellulose 4000), sodium alginate, xanthan gum, starch-sodium acrylate graft copolymers, as well as polyalkylene glycols (such as polyethylene glycols such as PEG20000), polydimethylsiloxane (A), and alkylene oxide adducts of aliphatic alcohols (B).

[0040] As the polymer (Y), one of the above polymers may be used alone, or two or more of them may be used in combination. For example, polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) may be used in combination, in which case the weighted average HLB value of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) [weighted average based on the weight ratio of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B)] is 7 or more.

[0041] As an example of the polymer (Y), a composition containing polydimethylsiloxane (A) and an alkylene oxide adduct of an aliphatic alcohol (B) [containing water (an additive described later) as a component other than the polymer (Y)] will be described.

[0042] Polydimethylsiloxane (A) is a dimethylsiloxane unit {-(CH 3 ) 2 The polymer includes those having a structure with a repeating unit of {SiO-}, and specifically includes those represented by the following general formula (1). CH 3 -[(CH 3 ) 2 SiO] n -Si-(CH 3 ) 3 (1) In general formula (1), n ​​is the number-average number of dimethylsiloxane units and is a number from 60 to 500, but is not necessarily an integer.

[0043] In the general formula (1), n ​​is preferably a number from 100 to 450, and more preferably a number from 150 to 400, from the viewpoint of spreadability.

[0044] As the polydimethylsiloxane (A), for example, DOW CORNING® Q7-9120 SILICONE FLUID “100CST (n=85)”, “350CST (n=200)” and “1000CST (n=350)” manufactured by Dow Corning Toray Co., Ltd. are commercially available and can be obtained.

[0045] As the polydimethylsiloxane (A), from the viewpoint of the durability of the effect of the bacterial flora improving agent, the polydimethylsiloxane represented by the above general formula (1) is preferable.

[0046] As the alkylene oxide adduct of an aliphatic alcohol (B), from the viewpoint of spreadability, the one represented by the following general formula (2) is preferable. R 1 -(OA) m -OH (2) In general formula (2), R 1 represents an alkyl group having 8 to 18 carbon atoms or an alkenyl group having 8 to 18 carbon atoms, OA represents an oxyalkylene group having 2 to 4 carbon atoms, and m represents the number-average molar number of oxyalkylene groups added, which is a number from 1 to 50 and is not necessarily an integer.

[0047] In the general formula (2), R 1 represents an alkyl group having 8 to 18 carbon atoms or an alkenyl group having 8 to 18 carbon atoms. The alkyl group having 8 to 18 carbon atoms includes a linear alkyl group having 8 to 18 carbon atoms and a branched alkyl group having 8 to 18 carbon atoms. Examples of the linear alkyl group having 8 to 18 carbon atoms include an n-octyl group, an n-decyl group, an n-undecyl group, an n-dodecyl group, an n-tridecyl group, an n-tetradecyl group, an n-pentadecyl group, an n-hexadecyl group, an n-heptadecyl group, and an n-octadecyl group. Examples of the branched alkyl group having 8 to 18 carbon atoms include a 2-ethylhexyl group, an isodecyl group, an isoundecyl group, an isododecyl group, an isotridecyl group, an isotetradecyl group, an isopentadecyl group, an isohexadecyl group, an isoheptadecyl group, and an isooctadecyl group.

[0048] The alkenyl group having 8 to 18 carbon atoms includes a linear alkenyl group having 8 to 18 carbon atoms and a branched alkenyl group having 8 to 18 carbon atoms. Examples of the linear alkenyl group having 8 to 18 carbon atoms include an n-octenyl group, an n-dodecenyl group, an n-hexadecenyl group, and an n-octadecenyl group. Examples of the branched alkenyl group having 8 to 18 carbon atoms include an isodecenyl group, an isododecenyl group, and an isooctadecenyl group.

[0049] R 1 From the viewpoint of spreadability, the alkyl group is preferably a linear alkyl group having 8 to 18 carbon atoms, and more preferably a linear alkyl group having 10 to 18 carbon atoms.

[0050] In the general formula (2), OA includes an oxyethylene group, an oxypropylene group, an oxybutylene group, and the like. From the viewpoint of spreadability, the OA is preferably an oxyethylene group.

[0051] In the general formula (2), m is preferably a number from 3 to 40 from the viewpoint of spreadability.

[0052] In the alkylene oxide adduct of an aliphatic alcohol (B), the HLB value is preferably from 8.5 to 11.0, more preferably from 9.0 to 10.5, from the viewpoint of spreadability.

[0053] The weight ratio of polydimethylsiloxane (A) to alkylene oxide adduct of aliphatic alcohol (B) {(A) / (B)} is preferably 85 / 15 to 40 / 60, and more preferably 80 / 20 to 35 / 65, from the viewpoints of spreadability and durability of effect.

[0054] From the viewpoint of the duration of the effect, the total content of the polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B) is preferably 0.1 to 85% by weight, more preferably 1 to 85% by weight, even more preferably 5 to 85% by weight, particularly preferably 40 to 85% by weight, and most preferably 50 to 80% by weight, based on the weight of the bacterial flora improver. From the viewpoint of the duration of the effect, the total content of the polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B) is preferably 30 to 99% by weight, more preferably 50 to 99% by weight, particularly preferably 80 to 99% by weight, and most preferably 90 to 99% by weight, based on the total weight of the substance (X) and the polymer (Y).

[0055] When the bacterial flora improver contains only the four components of the substance (X), polydimethylsiloxane (A), the alkylene oxide adduct of an aliphatic alcohol (B), and water, the total content of polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B) is, from the viewpoint of the duration of the effect, preferably 1 to 85 wt %, more preferably 5 to 85 wt %, particularly preferably 40 to 85 wt %, and most preferably 50 to 80 wt %, based on the total weight of polydimethylsiloxane (A), the alkylene oxide adduct of an aliphatic alcohol (B), and water.

[0056] An example of a method for producing a composition containing a polymer (Y) including polydimethylsiloxane (A) and an alkylene oxide adduct of an aliphatic alcohol (B) includes a step (I) of mixing polydimethylsiloxane (A), the alkylene oxide adduct of an aliphatic alcohol (B), and water.

[0057] It is preferable that the polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B) are mixed in advance. In the step of mixing the polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B), the temperature during mixing is preferably 20°C to 70°C, more preferably 25°C to 65°C, from the viewpoint of emulsifiability.

[0058] In step (I), the weight ratio of polydimethylsiloxane (A) to alkylene oxide adduct of aliphatic alcohol (B) {(A) / (B)} is preferably 85 / 15 to 40 / 60, and more preferably 80 / 20 to 35 / 65, from the viewpoints of spreadability and durability of effect.

[0059] In the step (I), the temperature of the water is preferably from 20°C to 70°C, more preferably from 25°C to 65°C, from the viewpoint of emulsifiability.

[0060] In step (I), the amount of water is preferably 15 to 99% by weight, and more preferably 20 to 99% by weight, based on the total weight of the polydimethylsiloxane (A), the alkylene oxide adduct of an aliphatic alcohol (B), and water, from the viewpoint of the durability of the effect.

[0061] In the step (I), from the viewpoint of gelation, it is preferable to carry out stirring with a planetary mixer. From the viewpoint of uniformity, the rotation speed of the planetary mixer is preferably 10 to 70 rpm for rotation and 5 to 40 rpm for revolution, and more preferably 15 to 60 rpm for rotation and 10 to 35 rpm for revolution. Examples of the stirring blade include a screw blade and a gate-type stirring blade, and from the viewpoint of uniformity, the gate-type stirring blade is preferred.

[0062] In step (I), when the mixture of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) is mixed with water, the water is preferably added in 5 to 50 portions, and more preferably in 10 to 40 portions, from the viewpoint of gelation. In addition, when mixing water in step (I), from the viewpoint of gelation, it is preferable to charge one portion of water, confirm that the appearance is sufficiently uniform, and then add the next portion of water.

[0063] When the bacterial flora improving agent of the present invention is used to improve the balance of oral bacterial flora, from the viewpoint of the durability of the effect, it is preferable that the polymer (Y) contains the following (YA) and / or (YB), and it is more preferable to use (YA) and (YB) in combination. <(YA)> It is a polymer (sodium carboxymethylcellulose, xanthan gum, sodium alginate, etc.) having an anionic group (carboxy group, carboxylate group, etc.) and has a weight average molecular weight of 50,000 to 3,000,000 (preferably 100,000 to 2,000,000), and may be a mixture of two or more types of polymers. <(YB)> (YB) is a component having an HLB value of 7 or more excluding the above-mentioned (YA), and satisfies the following conditions (1) and / or (2). (1) When (YB) is diluted with water to a concentration of 1% by weight, the viscosity of the solution (measured in the same manner as the viscosity of the bacterial flora improver described below, measured with a cone-plate type rotational viscometer at 37°C) is 1 mPa s or more and less than 500 mPa s (preferably 5 mPa s or more and 450 mPa s or less). (2) The weight average molecular weight is 10,000 to 80,000 (preferably 15,000 to 50,000). (YB) may be a mixture of two or more components.

[0064] When (YA) and (YB) are used in combination, the ratio by weight of (YA) to the weight of (YB) [(YA) / (YB)] is preferably from 0.001 to 0.2, and more preferably from 0.001 to 0.1.

[0065] [Preservative (Z)] The bacterial flora improving agent of the present invention also contains a preservative (Z). The preservative (Z) is at least one member selected from the group consisting of benzoic acid and its salts, paraoxybenzoic acid esters, phenoxyethanol, 1,2-pentanediol, and isopropylmethylphenol.

[0066] Examples of salts of benzoic acid include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; and salts with organic bases such as triethylamine, triethanolamine, and pyridine. Examples of the paraoxybenzoic acid ester include paraoxybenzoic acid alkyl ester (the number of carbon atoms in the alkyl is preferably 1 to 4). Examples of the paraoxybenzoic acid alkyl ester include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.

[0067] [Other ingredients] The bacterial flora improving agent of the present invention may contain optional components (additives) other than the above-mentioned substance (X), polymer (Y) and preservative (Z).

[0068] Examples of the additives include lubricants such as wax, antioxidants, UV absorbers, defoamers, preservatives, fragrances, solvents [water and organic solvents (ethanol, etc.)], anionic surfactants (S), and other bactericidal components.

[0069] The anionic surfactant (S) has an anionic group and an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms. Examples of the anionic group include a carboxy group and a carboxylate group. The chain aliphatic hydrocarbon group having 12 to 30 carbon atoms may be either saturated or unsaturated, and examples thereof include aliphatic hydrocarbon groups having 12 to 20 carbon atoms, such as a lauryl group, a myristyl group, a palmityl group, a stearyl group, an oleyl group, a linoleyl group, and an arachidyl group. Examples of the substituents on the hydrocarbon group include a hydroxyl group, an oxo group (=0), an alkoxy group, an alkenyloxy group, a combination thereof, etc. The number of the substituents on the hydrocarbon group may be, for example, 1, 2, 3, 4, or 5. Specific examples of the anionic surfactant (S) include sodium lauryl sulfate and sodium lauroyl sarcosine. The anionic surfactant (S) has a chemical formula weight or a weight average molecular weight of 1,000 or less.

[0070] In the bacterial flora improver of the present invention, the total weight of the anionic surfactant (S) is 0 to 2% by weight based on the total weight of the substance (X), from the viewpoint of the effect of the bacterial flora improver. The above 0 to 2% by weight means that no anionic surfactant (S) is contained, or if it is contained, the total weight of the anionic surfactant (S) is 2% by weight or less relative to the total weight of the substance (X).

[0071] When the additive contains a bactericidal component other than the anionic surfactant (S), the total weight of the bactericidal component other than the anionic surfactant (S) and the anionic surfactant (S) is preferably 2% by weight or less based on the total weight of the substance (X), from the viewpoint of the effect of the bacterial flora improver. Examples of the bactericidal components other than the anionic surfactant (S) include glycyrrhizinic acid (or a salt thereof), β-glycyrrhetinic acid, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, alkyldiaminoethylglycine chloride solution, chlorhexidine hydrochloride, chlorhexidine hydrochloride, triclosan, lysozyme chloride, and hinokitiol.

[0072] The content of the solvent in the bacterial flora improver is not particularly limited as long as it is within the range of the viscosity and worked penetration of the bacterial flora improver described below, and is preferably, for example, 5 to 99% by weight relative to the total weight of the bacterial flora improver. Moreover, the water content in the bacterial flora improver is preferably 5 to 99% by weight, and more preferably 30 to 99% by weight, based on the total weight of the bacterial flora improver, from the viewpoints of spreading ability and the effect of improving the bacterial flora balance. When the bacterial flora improver contains water, it is preferable that after the bacterial flora improver is produced by the method described below and allowed to stand at 25°C for 10 minutes, its appearance is visually uniform (not separated into two or more phases).

[0073] The upper limit of the content of additives other than the above-mentioned solvent in the bacterial flora improver is preferably 10% by weight or less, more preferably 8% by weight or less, and particularly preferably 1% by weight or less, based on the weight of polymer (Y) in the bacterial flora improver. The lower limit of the content of the additives other than the solvent in the bacterial flora improver is not particularly limited, but may be 0.1% by weight or more based on the weight of polymer (Y) in the bacterial flora improver.

[0074] [Bacterial flora improver]

[0075] The content (weight proportion) of the substance (X) is preferably 0.01 to 5% by weight, and more preferably 0.05 to 3% by weight, based on the weight of the bacterial flora improver. From the viewpoint of optimally imparting a high pathogenic bacterium-inhibiting effect, the content (weight proportion) of the substance (X) preferably has a lower limit of 0.01 wt %, and more preferably a lower limit of 0.05 wt %, based on the weight of the bacterial flora improver of the present invention. Furthermore, from the viewpoint of favorably maintaining non-pathogenic resident bacteria, the content of the substance (X) is preferably limited to an upper limit of 5 wt %, more preferably 3 wt %, based on the weight of the bacterial flora improver of the present invention. When a hydroxycarboxylic acid (a compound having a hydroxy group and a carboxy group, particularly citric acid) is used as compound (X2), the weight proportion of the hydroxycarboxylic acid as compound (X2) is preferably 1 wt % or more based on the weight of the bacterial flora improver, from the viewpoint of the effect of the bacterial flora improver.

[0076] The content of the substance (X) is preferably at least 1% by weight, more preferably at least 2% by weight, based on the weight of the polymer (Y) in the bacterial flora improver. The content of the substance (X) is preferably at most 200% by weight, more preferably at most 150% by weight, based on the weight of the polymer (Y) in the bacterial flora improver. The content of the substance (X) is preferably at most 1 to 200% by weight, more preferably at most 2 to 150% by weight, based on the weight of the polymer (Y) in the bacterial flora improver. By containing the substance (X) in the above range, it is possible to preferably impart the effects of having a high inhibitory effect on pathogenic bacteria while maintaining non-pathogenic resident bacteria, and being able to maintain the above performance for a long period of time.

[0077] The weight ratio of the substance (X) to the preservative (Z) [weight of substance (X) / weight of preservative (Z)] is preferably 0.5 to 200, from the viewpoint of the effect of the bacterial flora improving agent.

[0078] When the bacterial flora improver of the present invention contains zinc atoms and / or magnesium atoms (including cases where it contains a compound containing these atoms, such as zinc oxide), the total weight proportion of zinc atoms and magnesium atoms is preferably 0.5 wt % or less based on the total weight of the substance (X), from the viewpoint of the effect of the bacterial flora improver. Furthermore, when the bacterial flora improver of the present invention contains zinc atoms and / or magnesium atoms (including cases where it contains compounds containing these atoms), the total weight ratio of zinc atoms and magnesium atoms is preferably 0.005% by weight or less based on the weight of the bacterial flora improver, from the viewpoint of the effect of the bacterial flora improver.

[0079] The worked penetration of the bacterial flora improver of the present invention, measured according to JIS K 2220, is preferably 100 to 400. When it is 100 or more, the inhibitory effect on pathogenic bacteria is further improved. When it is 400 or less, the maintenance effect on non-pathogenic resident bacteria is improved. The worked penetration of the bacterial flora improving agent of the present invention, measured in accordance with JIS K 2220, is more preferably from 100 to 300, from the viewpoint of the durability of the effect.

[0080] The viscosity of the bacterial flora improving agent of the present invention at 37° C., as measured with a cone-plate type rotational viscometer, is preferably 1 to 4,000 Pa·s. Specifically, the viscosity is measured by the following measurement method. <Measurement conditions> Equipment: MCR302 (Anton Paar) Fixture: CP-25 (25mm diameter corn plate) Gap: 1mm ·Temperature: 37℃, Strain rate: 0.5 1 / s (rotation speed: 0.6 rpm) <Measurement method> Approximately 1.5 g of sample is placed on the sample stage and clamped with CP-25, the gap between the cone plates is set to 1 mm, and any excess sample is scraped off. After adjusting the temperature at 37°C for 1 minute, measurements are taken while varying the rotation speed from 0.1 to 10 rpm (20 plots at measurement intervals of 10 to 1 second). The viscosity value when the strain rate is 0.5 1 / s (rotation speed: 0.6 rpm) is recorded, and this value is regarded as the viscosity of the bacterial flora improver. When the above viscosity of the bacterial flora improver is 1 Pa s or more, the duration of the effect of the bacterial flora improver is further improved.When the above viscosity of the bacterial flora improver is 4,000 Pa s or less, the inhibitory effect on pathogenic bacteria is further improved. From the viewpoint of the durability of the effect, the above viscosity of the bacterial flora improving agent is more preferably from 10 to 4,000 Pa·s, and particularly preferably from 1,000 to 4,000 Pa·s. Moreover, from the viewpoint of spreading ability, the above-mentioned viscosity of the bacterial flora improving agent is preferably 2,000 to 3,700 Pa·s.

[0081] The pH of a solution obtained by diluting the bacterial flora improver of the present invention with water (ion-exchanged water or the like) so that the concentration is 1% by weight is preferably 6 to 8 from the viewpoint of the bacterial flora balance improving effect. The pH can be measured using a pH meter at 25°C.

[0082] The bacterial flora improver of the present invention can be produced by blending the respective components and mixing them uniformly at room temperature or, if necessary, by heating (for example, at 30 to 70° C.) The blending order and blending method of the respective components are not particularly limited.

[0083] [How to use] The bacterial flora improver of the present invention is a bacterial flora improver for improving the bacterial flora of mucosa and / or nail, and can be used by applying it to the affected area [mucous membrane {oral cavity (tongue, gums, gingiva, etc.), intestines, eyes, etc.}, nail (nail plate), etc.] or the area around the affected area with a finger or the like and leaving the bacterial flora improver at the affected area, and application to mucosa is particularly preferred. For example, when the bacterial flora improving agent of the present invention is applied to the mucous membranes of the oral cavity (tongue, gums, gingiva, etc.), it is expected to have the effect of preventing periodontal disease, which progresses through the stages of gingivitis and periodontitis. The bacterial flora improver of the present invention can be used as medicines, medical devices (medical adhesives and wound healing materials, etc.), quasi-drugs, cosmetics, foods, etc. by using a polymer appropriate for the application, and can improve the balance of the bacterial flora at the application site in all of the above applications. Specific examples of the above applications include toothpastes, oral gels, oral care foods, supplements, pet care products, and nail care products.

[0084] The present specification discloses the following:

[0085] The present disclosure (1) relates to a compound (X1) having two or more hydroxy groups contained in an oxo acid group, and a salt thereof; Compound (X2) having one hydroxy group contained in an oxo acid group and a salt thereof, A heterocyclic compound (X3) having no oxoacid group and a salt thereof, A substance (X) which is at least one selected from the group consisting of ketones (X4) having no oxo acid group; A polymer (Y); A bacterial flora improver comprising a preservative (Z), The compound (X1), the compound (X2), the heterocyclic compound (X3) and the ketone (X4) do not have an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms, the total mass ratio of the oxo acid groups, the hydroxy groups not contained in the oxo acid groups, the carbonyl groups not contained in the oxo acid groups, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton contained in the compound (X1) is 45 mass% or more based on the molecular weight of the compound (X1); the compound (X2) has an atom having an unshared electron pair (excluding atoms contained in an oxoacid group, and atoms contained in an amino group not constituting an imidazole skeleton and an amino group not constituting a pyridine skeleton), the total mass ratio of the oxo acid groups, the hydroxy groups not contained in the oxo acid groups, the carbonyl groups not contained in the oxo acid groups, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton contained in the compound (X2) is 55 mass% or more based on the molecular weight of the compound (X2); the heterocyclic compound (X3) has an imidazole skeleton or a pyridine skeleton and a hydroxy group and / or a carbonyl group, or has two or more skeletons selected from an imidazole skeleton and a pyridine skeleton, the total mass ratio of carbon atoms contained in the imidazole skeleton and the pyridine skeleton, nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton, hydroxy groups, and carbonyl groups contained in the imidazole skeleton and the pyridine skeleton of the heterocyclic compound (X3) is 50 mass% or more based on the molecular weight of the heterocyclic compound (X3); The ketone (X4) has a linear β-diketone structure, the total weight ratio of the hydroxyl groups and the carbonyl groups in the ketone (X4) is 30 mass% or more based on the molecular weight of the compound (X4); The formula weight of the substance (X) is 550 or less, The polymer (Y) has an HLB value of 7 or more and a weight average molecular weight of 10,000 to 3,000,000; the preservative (Z) is at least one selected from the group consisting of benzoic acid and its salts, paraoxybenzoic acid esters, phenoxyethanol, 1,2-pentanediol, and isopropylmethylphenol; the bacterial flora improver does not contain an anionic surfactant (S) or contains 2% by weight or less of an anionic surfactant (S) based on the total weight of the substance (X); the anionic surfactant (S) has an anionic group and an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms, The chemical formula weight or weight average molecular weight of the anionic surfactant (S) is 1000 or less. A bacterial flora improving agent for improving the bacterial flora of mucous membranes and / or nails.

[0086] The present disclosure (2) is the bacterial flora improver according to the present disclosure (1), wherein the weight ratio of the substance (X) to the preservative (Z) [weight of substance (X) / weight of preservative (Z)] is 0.5 to 200.

[0087] The present disclosure (3) is the bacterial flora improver according to the present disclosure (1) or (2), wherein the bacterial flora improver has a pH of 6 to 8 when diluted with water to a concentration of 1 wt %.

[0088] The present disclosure (4) is the bacterial flora improver according to any one of the present disclosures (1) to (3), wherein the weight proportion of the substance (X) is 0.01 to 5 wt % based on the weight of the bacterial flora improver. EXAMPLES

[0089] The present invention will be further described below with reference to examples and comparative examples, but the present invention is not limited thereto. In the following, unless otherwise specified, parts means parts by weight, and % means % by weight.

[0090] <Examples 1 to 61 and Comparative Examples 1 to 9: Production of bacterial flora improvers> The substance (X) [and / or (X')], polymer (Y), anionic surfactant (S), preservative (Z), and ion-exchanged water were mixed at 25°C to obtain the concentrations (wt %) shown in Tables 1 to 10.

[0091] <Description of each ingredient> The raw materials corresponding to each component used in the examples and comparative examples are as follows. [Substance (X)] (X-1): pentasodium triphosphate [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of total mass of oxo acid groups to molecular weight of triphosphate: 88% by mass] (X-2): Acetylacetone [Nacalai Tesque, Inc., ratio of total mass of carbonyl groups to molecular weight of acetylacetone: 56% by mass] (X-3): Benzoylacetone [MERCK, ratio of total mass of carbonyl groups to molecular weight of benzoylacetone: 35% by mass] (X-4): Levulinic acid [Tokyo Chemical Industry Co., Ltd., ratio of the total mass of oxoacid groups and carbonyl groups to the molecular weight of levulinic acid: 63% by mass] (X-5): Sodium tungstate dihydrate [Na 2 WO 4 2H 2 O, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxo acid groups to the molecular weight of tungstic acid: 100 mass%, substance (X) (Na 2 WO 4 Weight percentage of (X-5): 89% by weight based on the weight of (X-5) (X-6): Glycylglycine [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxoacid groups and carbonyl groups to the molecular weight of glycylglycine: 55% by mass] (X-7): glutamic acid [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of total mass of oxoacid groups to molecular weight of glutamic acid: 61% by mass] (X-8): Malic acid [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxoacid groups and hydroxyl groups to the molecular weight of malic acid: 80% by mass] (X-9): Citric acid [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxo acid groups and hydroxyl groups to the molecular weight of citric acid: 79% by mass] (X-10): Gluconic acid [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxoacid groups and hydroxyl groups to the molecular weight of gluconic acid: 66% by mass] (X-11): Glucuronic acid [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxoacid groups and hydroxyl groups to the molecular weight of glucuronic acid: 58% by mass] (X-12): Ethylenediaminetetraacetic acid [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of total mass of oxoacid groups to molecular weight of ethylenediaminetetraacetic acid: 62% by mass] (X-13): Iminodiacetic acid [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of total mass of oxo acid groups to molecular weight of iminodiacetic acid: 68% by mass] (X-14): 8-quinolinol [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., ratio of the total mass of carbon atoms, nitrogen atoms and hydroxyl groups contained in the pyridine skeleton to the molecular weight of 8-quinolinol: 63% by mass] (X-15): Tartaric acid [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., ratio of the total mass of oxo acid groups and hydroxyl groups to the molecular weight of tartaric acid: 83% by mass] (X-16): Adenosine triphosphate disodium trihydrate [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., the ratio of the total mass of the oxo acid group, hydroxyl group, and carbon and nitrogen atoms contained in the imidazole skeleton to the molecular weight of adenosine triphosphate: 61% by mass, the weight ratio of the substance (X) (adenosine triphosphate disodium) contained in (X-16): 91% by weight based on the weight of (X-16)] (X-17): disodium guanosine-5'-triphosphate [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., ratio of the total mass of the oxoacid group, hydroxyl group, and carbon and nitrogen atoms contained in the imidazole skeleton to the molecular weight of guanosine-5'-triphosphate: 59% by mass] (X-18): L-histidine hydrochloride monohydrate [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., ratio of the total mass of the oxo acid group, the carbon atom contained in the imidazole skeleton, and the nitrogen atom contained in the imidazole skeleton to the molecular weight of L-histidine: 70% by mass] (X-19): 1,10-phenanthroline monohydrate [manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., ratio of the total mass of carbon atoms and nitrogen atoms contained in the pyridine skeleton to the molecular weight of 1,10-phenanthroline: 88% by mass] [Substance (X')] (X'-1): Benzalkonium chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (X'-2): Benzethonium chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (X'-3): Dipotassium glycyrrhizinate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (X'-4): Cetylpyridinium chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (X'-5): Curcumin [Ratio of the total mass of hydroxyl groups and carbonyl groups to the molecular weight of curcumin: 24% by mass]

[0092] Polymer (Y-1): Xanthan gum [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., weight average molecular weight: 2,000,000, HLB value: 34.6] (Y-2): Starch-sodium acrylate graft copolymer [Product name: Sunfresh ST100, manufactured by Sanyo Chemical Industries, Ltd., weight average molecular weight 1,000,000, HLB value: 30.0] (Y-3): PEG20000 [Sanyo Chemical Industries, Ltd., weight average molecular weight 20,000, HLB value: 18.9] (Y-4): Hydroxypropyl methylcellulose 65SH [Shin-Etsu Chemical Co., Ltd., weight average molecular weight 300,000, HLB value: 10.2] (Y-5): Methylcellulose 4000 [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., weight average molecular weight 140,000, HLB value: 34.3] (Y-6): Sodium alginate [manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., weight average molecular weight 100,000, HLB value: 58.2]

[0093] [Anionic surfactant (S)] (S-1): Sodium lauroyl sarcosine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (S-2): Sodium lauryl sulfate

[0094] [Preservative (Z)] (Z-1): Sodium benzoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Z-2): Phenoxyethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Z-3): Methyl paraoxybenzoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Z-4): Ethyl paraoxybenzoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Z-5): Propyl paraoxybenzoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Z-6): Butyl paraoxybenzoate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Z-7): 1,2-pentanediol (Tokyo Chemical Industry Co., Ltd.) (Z-8): Isopropylmethylphenol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)

[0095] The viscosity and worked penetration of each bacterial flora improving agent were measured by the methods described in this specification. The results are shown in Tables 1 to 10. In addition, the pH of each solution diluted with ion-exchanged water to a concentration of 1% by weight of the bacterial flora improving agent was also measured. The results are shown in Tables 1 to 10.

[0096] In addition, for each substance (X), the amount (g) of magnesium captured per 100 g of substance (X) was measured by the ion electrode method using the method described in this specification. 2 WO 4 The amount of magnesium captured per 100 g of disodium adenosine triphosphate contained in (X-16), per 100 g of L-histidine hydrochloride contained in (X-18), and per 100 g of 1,10-phenanthroline contained in (X-19) was measured. The results are shown in Tables 1 to 10.

[0097] <Confirmation test for selective bacterial growth inhibition> The pathogenic bacteria used in the test were Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, Candida albicans, Candida glabrata, and Staphylococcus aureus, and the non-pathogenic bacteria were Streptococcus salivarius and Staphylococcus epidermidis. The media used to culture each bacterium were: modified GAM bouillon "Nissui" (manufactured by Nissui Pharmaceutical Co., Ltd.) supplemented with 1 μg / mL menadione for Porphyromonas gingivalis; modified GAM bouillon "Nissui" for Fusobacterium nucleatum, Prevotella intermedia, and Streptococcus salivarius; LB medium (manufactured by Becton Dickinson) for Staphylococcus aureus and Staphylococcus epidermidis; and YM medium (manufactured by Sigma) for Candida albicans and Candida glabrata. Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia were cultured under anaerobic conditions, while Streptococcus salivarius, Staphylococcus aureus, Staphylococcus epidermidis, Candida albicans, and Candida glabrata were cultured under aerobic conditions. 50 mg of each of the bacterial flora improvers prepared with the compositions shown in Tables 1 to 10 was dispensed into each well of a 24-well plate. When culturing under anaerobic conditions using the above media, each strain was cultured overnight at 37°C and diluted with the respective culture media so that the absorbance at 600 nm was 0.15, and 500 μL of each was dispensed into a 24-well plate containing a bacterial flora improver, and then statically cultured at 37°C under anaerobic conditions using Anaeropack Kenki 10% (Mitsubishi Gas Chemical Co., Ltd.). When culturing under aerobic conditions using the above media, each strain was cultured overnight with shaking at 37°C and diluted with the respective culture media so that the absorbance at 600 nm was 0.15, and 500 μL of each was dispensed into a 24-well plate containing a bacterial flora improver, and then statically cultured at 37°C. After 48 hours, the plates were collected and the growth of each bacterium was evaluated by measuring the absorbance at 600 nm. The proliferation inhibitory effect was expressed as a relative value when the turbidity when a mixture of the same weight of polymer (Y) and ion-exchanged water only [a composition obtained by removing substance (X) or (X') and preservative (Z) from each bacterial flora improver] was used instead of each bacterial flora improver was set to 1. The results are shown in Tables 1 to 10.

[0098] When the bacterial flora improver of the present invention is applied to the oral cavity, if the proliferation of Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia is inhibited compared to when the bacterial flora improver is not added, and the proliferation of Streptococcus salivarius remains unchanged compared to when the bacterial flora improver is not added, then the proliferation of the bacteria is selectively inhibited. For example, the above relative values ​​may be in the following ranges. An embodiment in which the test results for Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia are 0.01 to 0.30 (preferably 0.01 to 0.15), and the test result for Streptococcus salivarius is 0.8 to 1.2.

[0099] Furthermore, when the bacterial flora improver of the present invention is applied to a nail, if the proliferation of Staphylococcus aureus, Candida albicans, and Candida glabrata is inhibited compared to when the bacterial flora improver is not added, and the proliferation of Staphylococcus epidermidis remains unchanged compared to when the bacterial flora improver is not added, then the proliferation of the bacteria is selectively inhibited. For example, the above relative values ​​may be in the following ranges. An embodiment in which the test result for Staphylococcus aureus, Candida albicans, and Candida glabrata is 0.01 to 0.30 (preferably 0.01 to 0.15), and the test result for Staphylococcus epidermidis is 0.8 to 1.2.

[0100] <Evaluation of long-term storage stability> In order to confirm that the selective bacterial proliferation inhibition effect is stably maintained even during long-term storage, a long-term storage stability test was carried out using the bacterial flora improvers prepared in Examples 1 to 61 and Comparative Examples 1 to 9. In detail, each bacterial flora improver was stored at a temperature of 40°C and a relative humidity of 75% for 3 months (corresponding to 1 year and 6 months at room temperature) as an accelerated test. After that, the above-mentioned <Confirmation test for selective bacterial proliferation inhibition> was carried out using the stored bacterial flora improvers. In addition, in the confirmation test of selective bacterial growth inhibition after the accelerated test, the turbidity was expressed as a relative value when the turbidity of a mixture of only the polymer (Y) and ion-exchanged water [a composition obtained by removing the substances (X), (X'), anionic surfactant (S), and preservative (Z) from each bacterial flora improver] of the same weight before the accelerated test was used was set at 1. The results are shown in Tables 1 to 10. Moreover, in Comparative Examples 1 and 7, the measurement was impossible because of proliferation of unwanted bacteria after the accelerated test.

[0101] [Table 1]

[0102] [Table 2]

[0103] [Table 3]

[0104] [Table 4]

[0105] [Table 5]

[0106] [Table 6]

[0107] [Table 7]

[0108] [Table 8]

[0109] [Table 9]

[0110] [Table 10]

[0111] As shown in Tables 1 to 10, in the evaluation of Examples 1 to 61 containing the substance (X) and the preservative (Z), the proliferation of pathogenic bacteria was selectively inhibited while the proliferation of non-pathogenic bacteria was not inhibited, and an ideal balance of the bacterial flora was achieved, thereby confirming the effect of improving the bacterial flora. Furthermore, in Comparative Examples 2 to 6 which contained the substance (X) and / or the substance (X') but did not contain the preservative (Z), the effect of improving the bacterial flora deteriorated after the accelerated test, whereas in Examples 1 to 61, the effect of selectively inhibiting the growth of pathogenic bacteria and inhibiting the growth of non-pathogenic bacteria was maintained even after the accelerated test. In addition, in Comparative Example 8, which contains a preservative (Z) but a substance (X') instead of the substance (X), it was confirmed that the growth of non-pathogenic bacteria was inhibited. This suggests that the combined use of a specific substance (X) and a preservative (Z) is important in order to achieve both a selective bacterial inhibition effect and long-term storage stability. Moreover, in Comparative Example 9, in which the weight ratio of the anionic surfactant (S) to the weight of the substance (X) exceeded 2% by weight, it was confirmed that the proliferation of non-pathogenic bacteria was inhibited. It can be seen that the bacterial flora improving agent of the present invention has excellent long-term storage stability and has a selective growth inhibitory effect on pathogenic bacteria without affecting non-pathogenic bacteria.

Claims

1. Compound (X1) having two or more hydroxy groups contained in an oxo acid group and a salt thereof; Compound (X2) having one hydroxy group contained in an oxo acid group and a salt thereof, A heterocyclic compound (X3) having no oxoacid group and a salt thereof, a substance (X) which is at least one selected from the group consisting of ketones (X4) having no oxo acid group; A polymer (Y), A bacterial flora improver comprising a preservative (Z), The compound (X1), the compound (X2), the heterocyclic compound (X3) and the ketone (X4) do not have an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms, the total mass ratio of the oxo acid groups, the hydroxy groups not contained in the oxo acid groups, the carbonyl groups not contained in the oxo acid groups, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton contained in the compound (X1) is 45 mass% or more based on the molecular weight of the compound (X1); the compound (X2) has an atom having an unshared electron pair (excluding atoms contained in an oxoacid group, and atoms contained in an amino group not constituting an imidazole skeleton and an amino group not constituting a pyridine skeleton), the total mass ratio of the oxo acid group, the hydroxy group not contained in the oxo acid group, the carbonyl group not contained in the oxo acid group, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton contained in the compound (X2) is 55 mass% or more based on the molecular weight of the compound (X2); the heterocyclic compound (X3) has an imidazole skeleton or a pyridine skeleton and a hydroxy group and / or a carbonyl group, or has two or more skeletons selected from an imidazole skeleton and a pyridine skeleton, the total mass ratio of carbon atoms contained in the imidazole skeleton and the pyridine skeleton, nitrogen atoms contained in the imidazole skeleton and the pyridine skeleton, hydroxy groups, and carbonyl groups contained in the imidazole skeleton and the pyridine skeleton of the heterocyclic compound (X3) is 50 mass% or more based on the molecular weight of the heterocyclic compound (X3), The ketone (X4) has a linear β-diketone structure, the total weight ratio of the hydroxyl groups and the carbonyl groups in the ketone (X4) is 30 mass% or more based on the molecular weight of the compound (X4), The chemical formula weight of the substance (X) is 550 or less; The polymer (Y) has an HLB value of 7 or more and a weight average molecular weight of 10,000 to 3,000,000; the preservative (Z) is at least one selected from the group consisting of benzoic acid and its salts, paraoxybenzoic acid esters, phenoxyethanol, 1,2-pentanediol, and isopropylmethylphenol; the bacterial flora improver does not contain an anionic surfactant (S) or contains 2 wt % or less of an anionic surfactant (S) based on the total weight of the substance (X); the anionic surfactant (S) has an anionic group and an optionally substituted chain aliphatic hydrocarbon group having 12 to 30 carbon atoms, The chemical formula weight or weight average molecular weight of the anionic surfactant (S) is 1000 or less. A bacterial flora improving agent for improving the bacterial flora of mucous membranes and / or nails.

2. 2. The bacterial flora improver according to claim 1, wherein a weight ratio of the substance (X) to the preservative (Z) [weight of substance (X) / weight of preservative (Z)] is 0.5 to 200.

3. The bacterial flora improver according to claim 1 or 2, wherein the pH of a solution of the bacterial flora improver diluted with water to a concentration of 1% by weight is 6 to 8.

4. The bacterial flora improver according to claim 1 or 2, wherein the weight proportion of the substance (X) is 0.01 to 5% by weight based on the weight of the bacterial flora improver.

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